Use of adhesive cranial bone flap fixation without hardware to improve mechanical strength, resist cerebrospinal fluid leakage, and maintain anatomical alignment: a laboratory study.

OBJECTIVE: Titanium plates and screws (TPS) are the current standard of care for fixation of cranial bone flaps. These materials have been used for decades but have known potential complications, including flap migration, bone resorption/incomplete osseous union, hardware protrusion, cosmetic deformity, wound infection/dehiscence, and cerebrospinal fluid (CSF) leakage. This study evaluated the efficacy of a novel mineral-organic bone adhesive (Tetranite) for cranial bone flap fixation. METHODS: Craniotomy bone flaps created in human cadaveric skulls were tested under quasistatic and impact loading in the following conditions: 1) uncut skull; 2) bone flaps fixated with TPS alone; and 3) bone flaps fixated with bone adhesive alone. All fixative surgical procedures were performed by a group of 16 neurosurgeons in a simulated surgical environment. The position of adhesive-fixated cranial bone flaps was measured using computed tomography and compared with their original native location. The resistance of adhesive-fixated cranial bone flaps to simulated CSF leakage was also evaluated. Because there was a gap around the circumference of the TPS-fixated specimens that was visible to the naked eye, pressurized CSF leak testing was not attempted on them. RESULTS: Adhesive-fixated bone flaps showed significantly stiffer and stronger quasistatic responses than TPS-fixated specimens. The strength and stiffness of the adhesive-fixated specimens were not significantly different from those of the uncut native skulls. Total and plastic deflections under 6-J impact were significantly less for adhesive-fixed bone flaps than TPS. There were no significant differences in any subthreshold impact metrics between the adhesive-fixed and native specimens at both 6-J and 12-J impact levels, with 1 exception. Plastic deflection at 6-J impact was significantly less in adhesive-fixated bone flaps than in native specimens. The energy to failure of the adhesive-fixated specimens was not significantly different from that of the native specimens. Time since fixation (20 minutes vs 10 days) did not significantly affect the impact failure properties of the adhesive-fixated specimens. Of the 16 adhesive-fixated craniotomy specimens tested, 14 did not leak at pressures as high as 40 mm Hg. CONCLUSIONS: The neurosurgeons in this study had no prior exposure or experience with the bone adhesive. Despite this, improved resistance to CSF egress, superior mechanical properties, and better cosmetic outcomes were demonstrated with bone adhesive compared with TPS.

Cranial flap fixation in sheep using a resorbable bone adhesive.

OBJECTIVE: The authors' goal in this study was to investigate the use of a novel, bioresorbable, osteoconductive, wet-field mineral-organic bone adhesive composed of tetracalcium phosphate and phosphoserine (TTCP-PS) for cranial bone flap fixation and compare it with conventional low-profile titanium plates and self-drilling screws. METHODS: An ovine craniotomy surgical model was used to evaluate the safety and efficacy of TTCP-PS over 2 years. Bilateral cranial defects were created in 41 sheep and were replaced in their original position. The gaps (kerfs) were completely filled with TTCP-PS (T1 group), half-filled with TTCP-PS (T2 group), or left empty and the flaps fixated by plates and screws as a control (C group). At 12 weeks, 1 year, and 2 years following surgery, the extent of bone healing, local tissue effects, and remodeling of the TTCP-PS were analyzed using macroscopic observations and histopathological and histomorphometric analyses. Flap fixation strength was evaluated by biomechanical testing at 12 weeks and 1 year postoperatively. RESULTS: No adverse local tissue effects were observed in any group. At 12 weeks, the bone flap fixation strengths in test group 1 (1689 ± 574 N) and test group 2 (1611 ± 501 N) were both statistically greater (p = 0.01) than that in the control group (663 ± 385 N). From 12 weeks to 1 year, the bone flap fixation strengths increased significantly (p < 0.05) for all groups. At 1 year, the flap fixation strength in test group 1 (3240 ± 423 N) and test group 2 (3212 ± 662 N) were both statistically greater (p = 0.04 and p = 0.02, respectively) than that in the control group (2418 ± 1463 N); however, there was no statistically significant difference in the strengths when comparing the test groups at both timepoints. Test group 1 had the best overall performance based on histomorphometric evaluation and biomechanical testing. At 2 years postoperatively, the kerfs filled with TTCP-PS had histological evidence of osteoconduction and replacement of TTCP-PS by bone with nearly complete osteointegration. CONCLUSIONS: TTCP-PS was demonstrated to be safe and effective for cranial flap fixation in an ovine model. In this study, the bioresorbable, osteoconductive bone adhesive appeared to have multiple advantages over standard plate-and-screw bone flap fixation, including biomechanical superiority, more complete and faster bony healing across the flap kerfs without fibrosis, and the minimization of bone flap and/or hardware migration and loosening. These properties of TTCP-PS may improve human cranial bone flap fixation and cranioplasty.

Geographic variations in clinical presentation and outcomes of decompressive surgery in patients with symptomatic degenerative cervical myelopathy: analysis of a prospective, international multicenter cohort study of 757 patients.

BACKGROUND CONTEXT: Degenerative cervical myelopathy (DCM) is a progressive degenerative spine disease and the most common cause of spinal cord impairment in adults worldwide. Few studies have reported on regional variations in demographics, clinical presentation, disease causation, and surgical effectiveness. PURPOSE: The objective of this study was to evaluate differences in demographics, causative pathology, management strategies, surgical outcomes, length of hospital stay, and complications across four geographic regions. STUDY DESIGN/SETTING: This is a multicenter international prospective cohort study. PATIENT SAMPLE: This study includes a total of 757 symptomatic patients with DCM undergoing surgical decompression of the cervical spine. OUTCOME MEASURES: The outcome measures are the Neck Disability Index (NDI), the Short Form 36 version 2 (SF-36v2), the modified Japanese Orthopaedic Association (mJOA) scale, and the Nurick grade. MATERIALS AND METHODS: The baseline characteristics, disease causation, surgical approaches, and outcomes at 12 and 24 months were compared among four regions: Europe, Asia Pacific, Latin America, and North America. RESULTS: Patients from Europe and North America were, on average, older than those from Latin America and Asia Pacific (p=.0055). Patients from Latin America had a significantly longer duration of symptoms than those from the other three regions (p<.0001). The most frequent causes of myelopathy were spondylosis and disc herniation. Ossification of the posterior longitudinal ligament was most prevalent in Asia Pacific (35.33%) and in Europe (31.75%), and hypertrophy of the ligamentum flavum was most prevalent in Latin America (61.25%). Surgical approaches varied by region; the majority of cases in Europe (71.43%), Asia Pacific (60.67%), and North America (59.10%) were managed anteriorly, whereas the posterior approach was more common in Latin America (66.25%). At the 24-month follow-up, patients from North America and Asia Pacific exhibited greater improvements in mJOA and Nurick scores than those from Europe and Latin America. Patients from Asia Pacific and Latin America demonstrated the most improvement on the NDI and SF-36v2 PCS. The longest duration of hospital stay was in Asia Pacific (14.16 days), and the highest rate of complications (34.9%) was reported in Europe. CONCLUSIONS: Regional differences in demographics, causation, and surgical approaches are significant for patients with DCM. Despite these variations, surgical decompression for DCM appears effective in all regions. Observed differences in the extent of postoperative improvements among the regions should encourage the standardization of care across centers and the development of international guidelines for the management of DCM.

Biodegradable scaffolds promote tissue remodeling and functional improvement in non-human primates with acute spinal cord injury.

Tissue loss significantly reduces the potential for functional recovery after spinal cord injury. We previously showed that implantation of porous scaffolds composed of a biodegradable and biocompatible block copolymer of Poly-lactic-co-glycolic acid and Poly-l-lysine improves functional recovery and reduces spinal cord tissue injury after spinal cord hemisection injury in rats. Here, we evaluated the safety and efficacy of porous scaffolds in non-human Old-World primates (Chlorocebus sabaeus) after a partial and complete lateral hemisection of the thoracic spinal cord. Detailed analyses of kinematics and muscle activity revealed that by twelve weeks after injury fully hemisected monkeys implanted with scaffolds exhibited significantly improved recovery of locomotion compared to non-implanted control animals. Twelve weeks after injury, histological analysis demonstrated that the spinal cords of monkeys with a hemisection injury implanted with scaffolds underwent appositional healing characterized by a significant increase in remodeled tissue in the region of the hemisection compared to non-implanted controls. The number of glial fibrillary acidic protein immunopositive astrocytes was diminished within the inner regions of the remodeled tissue layer in treated animals. Activated macrophage and microglia were present diffusely throughout the remodeled tissue and concentrated at the interface between the preserved spinal cord tissue and the remodeled tissue layer. Numerous unphosphorylated neurofilament H and neuronal growth associated protein positive fibers and myelin basic protein positive cells may indicate neural sprouting inside the remodeled tissue layer of treated monkeys. These results support the safety and efficacy of polymer scaffolds in a primate model of acute spinal cord injury. A device substantially similar to the device described here is the subject of an ongoing human clinical trial.

Sustained Local Release of Methylprednisolone From a Thiol-Acrylate Poly(Ethylene Glycol) Hydrogel for Treating Chronic Compressive Radicular Pain.

STUDY DESIGN: A preclinical animal model of chronic ligation of the sciatic nerve was used to compare the effectiveness of a slow-release hydrogel carrying methylprednisolone to methylprednisolone injection alone, which simulates the current standard of care for chronic compressive radiculopathy (CR). OBJECTIVE: To extend the short-term benefits of steroid injections by using a nonswelling, biodegradable hydrogel as carrier to locally release methylprednisolone in a regulated and sustained way at the site of nerve compression. SUMMARY OF BACKGROUND DATA: CR affects millions worldwide annually, and is a cause of costly disability with significant societal impact. Currently, a leading nonsurgical therapy involves epidural injection of steroids to temporarily alleviate the pain associated with CR. However, an effective way to extend the short-term effect of steroid treatment to address the chronic component of CR does not exist. METHODS: We induced chronic compression injury of the sciatic nerves of rats by permanent ligation. Forty-eight hours later we injected our methylprednisolone infused hydrogel and assessed the effectiveness of our treatment for 4 weeks. We quantified mechanical hyperalgesia using a Dynamic Plantar Aesthesiometer (Ugo Basile, Stoelting Co., IL, USA), whereas gait analysis was conducted using the Catwalk automated gait analysis platform (Noldus, Leesburg, VA, USA). Macrophage staining was performed with immunohistochemistry and quantification of monocyte chemoattractant protein-1 in sciatic nerve lysates was performed with multiplex immunoassay using a SECTOR Imager 2400A (Meso Scale Discovery, Rockville, MA, USA). RESULTS: We demonstrate that using the hydrogel to deliver methylprednisolone results in significant (P < 0.05) reduction of hyperalgesia and improvement in the gait pattern of animals with chronic lesions as compared with animals treated with steroid alone. In addition, animals treated with hydrogel plus steroid showed significant reduction in the number of infiltrating macrophages at the sciatic nerve and reduced expression of the neuroinflammatory chemokine monocyte chemoattractant protein-1 (P < 0.05). CONCLUSION: Use of hydrogels as carriers for sustained local release of steroids provides significantly better control of pain in an animal model of chronic CR. Our steroid-infused hydrogel could be an effective extender of the short-term benefits of epidural steroid injections for patients with chronic compression-induced radicular pain. LEVEL OF EVIDENCE: N/A.

Mild diabetes is not a contraindication for surgical decompression in cervical spondylotic myelopathy: results of the AOSpine North America multicenter prospective study (CSM).

BACKGROUND CONTEXT: Cervical spondylotic myelopathy (CSM) is a chronic spinal cord disease and can lead to progressive or stepwise neurologic decline. Several factors may influence this process, including extent of spinal cord compression, duration of symptoms, and medical comorbidities. Diabetes is a systemic disease that can impact multiple organ systems, including the central and peripheral nervous systems. There has been little information regarding the effect of diabetes on patients with coexistent CSM. PURPOSE: To provide empirical data regarding the effect of diabetes on treatment outcomes in patients who underwent surgical decompression for coexistent CSM. STUDY DESIGN/SETTING: Large prospective multicenter cohort study of patients with and without diabetes who underwent decompressive surgery for CSM. PATIENT SAMPLE: Two hundred thirty-six patients without and 42 patients with diabetes were enrolled. Of these, 37 were mild cases and five were moderate cases. Four required insulin. There were no severe cases associated with end-organ damage. OUTCOME MEASURES: Self-report measures include Neck Disability Index and version 2 of 36-Item Short Form Health Survey (SF-36v2), and functional measures include modified Japanese Orthopedic Association (mJOA) score and Nurick grade. METHODS: We compared presurgery symptoms and treatment outcomes between patients with and without diabetes using univariate and multivariate models, adjusting for demographics and comorbidities. RESULTS: Diabetic patients were older, less likely to smoke, and more likely to be on social security disability insurance. Patients with diabetes presented with a worse Nurick grade, but there were no differences in mJOA and SF-36v2 at presentation. Overall, there was a significant improvement in all outcome parameters at 12 and 24 months. There was no difference in the level of improvement between the patients with and without diabetes, except in the SF-36v2 Physical Functioning, in which diabetic patients experienced significantly less improvement. There were no differences in surgical complication rates between diabetic patients and nondiabetic patients. CONCLUSIONS: Except for a worse Nurick grade, diabetes does not seem to affect severity of symptoms at presentation for surgery. More importantly, with the exception of the SF-36v2 Physical Functioning scores, outcomes of surgical treatment are similar in patients with diabetes and without diabetes. Surgical decompression is effective and should be offered to patients with diabetes who have symptomatic CSM and are appropriate surgical candidates.

Anterior versus posterior surgical approaches to treat cervical spondylotic myelopathy: outcomes of the prospective multicenter AOSpine North America CSM study in 264 patients.

STUDY DESIGN: A prospective observational multicenter study. OBJECTIVE: To help solve the debate regarding whether the anterior or posterior surgical approach is optimal for patients with cervical spondylotic myelopathy (CSM). SUMMARY OF BACKGROUND DATA: The optimal surgical approach to treat CSM remains debated with varying opinions favoring anterior versus posterior surgical approaches. We present an analysis of a prospective observational multicenter study examining outcomes of surgical treatment for CSM. METHODS: A total of 278 subjects from 12 sites in North America received anterior/posterior or combined surgery at the discretion of the surgeon. This study focused on subjects who had either anterior or posterior surgery (n = 264, follow-up rate, 87%). Outcome measures included the modified Japanese Orthopedic Assessment scale, the Nurick scale, the Neck Disability Index, and the Short-Form 36 (SF-36) Health Survey version 2 Physical and Mental Component Scores. RESULTS: One hundred and sixty-nine patients were treated anteriorly and 95 underwent posterior surgery. Anterior surgical cases were younger and had less severe myelopathy as assessed by mJOA and Nurick scores. There were no baseline differences in Neck Disability Index or SF-36 between the anterior and posterior cases. Improvement in the mJOA was significantly lower in the anterior group than posterior group (2.47 vs. 3.62, respectively, P < 0.01), although the groups started at different levels of baseline impairment. The extent of improvement in the Nurick Scale, Neck Disability Index, SF-36 version 2 Physical Component Score, and SF-36 version 2 Mental Component Score did not differ between the groups. CONCLUSION: Patients with CSM show significant improvements in several health-related outcome measures with either anterior or posterior surgery. Importantly, patients treated with anterior techniques were younger, with less severe impairment and more focal pathology. We demonstrate for the first time that, when patient and disease factors are controlled for, anterior and posterior surgical techniques have equivalent efficacy in the treatment of CSM. LEVEL OF EVIDENCE: 3.

Efficacy and safety of surgical decompression in patients with cervical spondylotic myelopathy: results of the AOSpine North America prospective multi-center study.

BACKGROUND: Cervical spondylotic myelopathy is the leading cause of spinal cord dysfunction worldwide. The objective of this study was to evaluate the impact of surgical decompression on functional, quality-of-life, and disability outcomes at one year after surgery in a large cohort of patients with this condition. METHODS: Adult patients with symptomatic cervical spondylotic myelopathy and magnetic resonance imaging evidence of spinal cord compression were enrolled at twelve North American centers from 2005 to 2007. At enrollment, the myelopathy was categorized as mild (modified Japanese Orthopaedic Association [mJOA] score ≥ 15), moderate (mJOA = 12 to 14), or severe (mJOA < 12). Patients were followed prospectively for one year, at which point the outcomes of interest included the mJOA score, Nurick grade, Neck Disability Index (NDI), and Short Form-36 version 2 (SF-36v2). All outcomes at one year were compared with the preoperative values with use of univariate paired statistics. Outcomes were also compared among the severity classes with use of one-way analysis of variance. Finally, a multivariate analysis that adjusted for baseline differences among the severity groups was performed. Treatment-related complication data were collected and the overall complication rate was calculated. RESULTS: Eighty-five (30.6%) of the 278 enrolled patients had mild cervical spondylotic myelopathy, 110 (39.6%) had moderate disease, and 83 (29.9%) had severe disease preoperatively. One-year follow-up data were available for 222 (85.4%) of 260 patients. There was a significant improvement from baseline to one year postoperatively (p < 0.05) in the mJOA score, Nurick grade, NDI score, and all SF-36v2 health dimensions (including the mental and physical health composite scores) except general health. With the exception of the change in the mJOA, the degree of improvement did not depend on the severity of the preoperative symptoms. These results remained unchanged after adjusting for relevant confounders in the multivariate analysis. Fifty-two patients experienced complications (prevalence, 18.7%), with no significant differences among the severity groups. CONCLUSIONS: Surgical decompression for the treatment of cervical spondylotic myelopathy was associated with improvement in functional, disability-related, and quality-of-life outcomes at one year of follow-up for all disease severity categories. Furthermore, complication rates observed in the study were commensurate with those in previously reported cervical spondylotic myelopathy series.

Perioperative and delayed complications associated with the surgical treatment of cervical spondylotic myelopathy based on 302 patients from the AOSpine North America Cervical Spondylotic Myelopathy Study.

OBJECT: Rates of complications associated with the surgical treatment of cervical spondylotic myelopathy (CSM) are not clear. Appreciating these risks is important for patient counseling and quality improvement. The authors sought to assess the rates of and risk factors associated with perioperative and delayed complications associated with the surgical treatment of CSM. METHODS: Data from the AOSpine North America Cervical Spondylotic Myelopathy Study, a prospective, multicenter study, were analyzed. Outcomes data, including adverse events, were collected in a standardized manner and externally monitored. Rates of perioperative complications (within 30 days of surgery) and delayed complications (31 days to 2 years following surgery) were tabulated and stratified based on clinical factors. RESULTS: The study enrolled 302 patients (mean age 57 years, range 29-86) years. Of 332 reported adverse events, 73 were classified as perioperative complications (25 major and 48 minor) in 47 patients (overall perioperative complication rate of 15.6%). The most common perioperative complications included minor cardiopulmonary events (3.0%), dysphagia (3.0%), and superficial wound infection (2.3%). Perioperative worsening of myelopathy was reported in 4 patients (1.3%). Based on 275 patients who completed 2 years of follow-up, there were 14 delayed complications (8 minor, 6 major) in 12 patients, for an overall delayed complication rate of 4.4%. Of patients treated with anterior-only (n = 176), posterior-only (n = 107), and combined anterior-posterior (n = 19) procedures, 11%, 19%, and 37%, respectively, had 1 or more perioperative complications. Compared with anterior-only approaches, posterior-only approaches had a higher rate of wound infection (0.6% vs 4.7%, p = 0.030). Dysphagia was more common with combined anterior-posterior procedures (21.1%) compared with anterior-only procedures (2.3%) or posterior-only procedures (0.9%) (p < 0.001). The incidence of C-5 radiculopathy was not associated with the surgical approach (p = 0.8). The occurrence of perioperative complications was associated with increased age (p = 0.006), combined anterior-posterior procedures (p = 0.016), increased operative time (p = 0.009), and increased operative blood loss (p = 0.005), but it was not associated with comorbidity score, body mass index, modified Japanese Orthopaedic Association score, smoking status, anterior-only versus posterior-only approach, or specific procedures. Multivariate analysis of factors associated with minor or major complications identified age (OR 1.029, 95% CI 1.002-1.057, p = 0.035) and operative time (OR 1.005, 95% CI 1.002-1.008, p = 0.001). Multivariate analysis of factors associated with major complications identified age (OR 1.054, 95% CI 1.015-1.094, p = 0.006) and combined anterior-posterior procedures (OR 5.297, 95% CI 1.626-17.256, p = 0.006). CONCLUSIONS: For the surgical treatment of CSM, the vast majority of complications were treatable and without long-term impact. Multivariate factors associated with an increased risk of complications include greater age, increased operative time, and use of combined anterior-posterior procedures.

Impact of capacity reductions in acute public-sector inpatient psychiatric services.

OBJECTIVE: This study tested the hypothesis that reductions in acute public-sector psychiatric inpatient capacity in a major urban area would be associated with negative impacts on patients and the community. METHODS: The impact of two discrete service changes that reduced acute inpatient capacity by 50% in a single public-sector general hospital setting was examined. Indicators of impact were obtained from existing administrative databases for a 33-month period. Indicators included measures of utilization and case mix on the acute inpatient and psychiatric emergency services, suicides among community mental health clients, and psychiatric evaluations conducted in county jails. RESULTS: Reductions in inpatient capacity were not associated with hypothesized negative impacts, such as increased demand for psychiatric emergency services, decreased access to emergency or inpatient services, or increased recidivism to inpatient care. Similarly, neither the number of suicides among community mental health clients nor the number of jail psychiatric evaluations increased after capacity reduction. CONCLUSIONS: Data from a single urban public-sector setting suggest that acute inpatient psychiatric capacity may be reduced without negative impacts on patients or the community. In this setting, collaboration between inpatient and outpatient providers to speed discharge facilitated reductions in inpatient length of stay that made it possible to serve the same number of patients with fewer resources. Other service system adjustments may be more appropriate in other settings, and alternative approaches to reducing utilization of high-cost inpatient care warrant examination.

Factors affecting psychiatric inpatient hospitalization from a psychiatric emergency service.

OBJECTIVE: As a gateway to the mental health system, psychiatric emergency services (PES) are charged with assessing a heterogeneous array of short-term and long-term psychiatric crises. However, few studies have examined factors associated with inpatient psychiatric hospitalization following PES in a racially diverse sample. We examine the demographic, service use and clinical factors associated with inpatient hospitalization and differences in predisposing factors by race and ethnicity. METHOD: Three months of consecutive admissions to San Francisco's only 24-h PES (N = 1,305) were reviewed. Logistic regression was used to estimate the associations between demographic, service use, and clinical factors and inpatient psychiatric hospitalization. We then estimated separate models for Asians, Blacks, Latinos and Whites. RESULTS: Clinical severity was a consistent predictor of hospitalization. However, age, gender, race/ethnicity, homelessness and employment status were all significant related to hospitalization. Alcohol and drug use were associated with lower probability of inpatient admission, however specific substances appear particularly salient for different racial/ethnic groups. DISCUSSION: While clinical characteristics played an essential role in disposition decisions, these results point to the importance of factors external to PES. Individual and community factors that affect use of psychiatric emergency services merit additional focused attention.

The treatment of symptomatic osteoporotic spinal compression fractures.

This clinical practice guideline is based on a series of systematic reviews of published studies on the treatment of symptomatic osteoporotic spinal compression fractures. Of 11 recommendations, one is strong; one, moderate; three, weak; and six, inconclusive. The strong recommendation is against the use of vertebroplasty to treat the fractures; the moderate recommendation is for the use of calcitonin for 4 weeks following the onset of fracture. The weak recommendations address the use of ibandronate and strontium ranelate to prevent additional symptomatic fractures, the use of L2 nerve root blocks to treat the pain associated with L3 or L4 fractures, and the use of kyphoplasty to treat symptomatic fractures in patients who are neurologically intact.

An injectable thiol-acrylate poly(ethylene glycol) hydrogel for sustained release of methylprednisolone sodium succinate.

Clinically available injectable hydrogels face technical challenges associated with swelling after injection and toxicity from unreacted constituents that impede their performance as surgical biomaterials. To overcome these challenges, we developed a system where chemical gelation was controlled by a conjugate Michael addition between thiol and acrylate in aqueous media, with 97% monomer conversion and 6 wt.% sol fraction. The hydrogel exhibited syneresis on equilibration, reducing to 59.7% of its initial volume. It had mechanical properties similar to soft human tissue with an elastic modulus of 189.8 kPa. Furthermore, a mesh size of 6.9 nm resulted in sustained release of methylprednisolone sodium succinate with a loading efficiency of 2 mg/mL. Functionalization with 50 µg/mL of an oligolysine peptide resulted in attachment of freshly isolated murine mesenchymal stem cells. The rational design of the physical, chemical and biological properties of the hydrogel makes it a potentially promising candidate for injectable applications.

Establishing a model spinal cord injury in the African green monkey for the preclinical evaluation of biodegradable polymer scaffolds seeded with human neural stem cells.

Given the involvement of post-mitotic neurons, long axonal tracts and incompletely elucidated injury and repair pathways, spinal cord injury (SCI) presents a particular challenge for the creation of preclinical models to robustly evaluate longitudinal changes in neuromotor function in the setting in the presence and absence of intervention. While rodent models exhibit high degrees of spontaneous recovery from SCI injury, animal care concerns preclude complete cord transections in non-human primates and other larger vertebrate models. To overcome such limitations a segmental thoracic (T9-T10) spinal cord hemisection was created and characterized in the African green monkey. Physiological tolerance of the model permitted behavioral analyses for a prolonged period post-injury, extending to predefined study termination points at which histological and immunohistochemical analyses were performed. Four monkeys were evaluated (one receiving no implant at the lesion site, one receiving a poly(lactide-co-glycolide) (PLGA) scaffold, and two receiving PLGA scaffolds seeded with human neural stem cells (hNSC)). All subjects exhibited Brown-Séquard syndrome 2 days post-injury consisting of ipsilateral hindlimb paralysis and contralateral hindlimb hypesthesia with preservation of bowel and bladder function. A 20-point observational behavioral scoring system allowed quantitative characterization of the levels of functional recovery. Histological endpoints including silver degenerative staining and Iba1 immunohistochemistry, for microglial and macrophage activation, were determined to reliably define lesion extent and correlate with neurobehavioral data, and justify invasive telemetered electromyographic and kinematic studies to more definitively address efficacy and mechanism.

Blockade of peroxynitrite-induced neural stem cell death in the acutely injured spinal cord by drug-releasing polymer.

Therapeutic impact of neural stem cells (NSCs) for acute spinal cord injury (SCI) has been limited by the rapid loss of donor cells. Neuroinflammation is likely the cause. As there are close temporal-spatial correlations between the inducible nitric oxide (NO) synthase expression and the donor NSC death after neurotrauma, we reasoned that NO-associated radical species might be the inflammatory effectors which eliminate NSC grafts and kill host neurons. To test this hypothesis, human NSCs (hNSCs: 5 x 10(4) to 2 x 10(6) per milliliter) were treated in vitro with "plain" medium, 20 microM glutamate, or donors of NO and peroxynitrite (ONOO(-); 100 and 400 microM of spermine or DETA NONOate, and SIN-1, respectively). hNSC apoptosis primarily resulted from SIN-1 treatment, showing ONOO(-)-triggered protein nitration and the activation of p38 MAPK, cytochrome c release, and caspases. Therefore, cell death following post-SCI (p.i.) NO surge may be mediated through conversion of NO into ONOO(-). We subsequently examined such causal relationship in a rat model of dual penetrating SCI using a retrievable design of poly-lactic-co-glycolic acid (PLGA) scaffold seeded with hNSCs that was shielded by drug-releasing polymer. Besides confirming the ONOO(-)-induced cell death signaling, we demonstrated that cotransplantation of PLGA film embedded with ONOO(-) scavenger, manganese (III) tetrakis (4-benzoic acid) porphyrin, or uric acid (1 micromol per film), markedly protected hNSCs 24 hours p.i. (total: n = 10). Our findings may provide a bioengineering approach for investigating mechanisms underlying the host microenvironment and donor NSC interaction and help formulate strategies for enhancing graft and host cell survival after SCI.

Risk factors for false positive transcranial motor evoked potential monitoring alerts during surgical treatment of cervical myelopathy.

STUDY DESIGN: Retrospective consecutive series review. OBJECTIVE: To examine performance of transcranial motor-evoked potential (TcMEP) monitoring in patients undergoing surgery for cervical myelopathy and potential risk factors for false positive alerts. SUMMARY OF BACKGROUND DATA: Although use of TcMEP monitoring has been increasing and has been specifically recommended in patients with cervical myelopathy, rates and risk factors for false positive alerts have not been established. METHODS: Intraoperative neuromonitoring data for 52 consecutive patients undergoing surgery for cervical myelopathy were reviewed. All major TcMEP alerts were identified. Comprehensive demographic and clinical data, preoperative imaging studies, operative, and anesthesia records were reviewed. RESULTS: Six of 52 patients (12%) experienced a major TcMEP alert consisting of sustained >80% loss of amplitude. There were no somatosensory-evoked potential (SSEP)-related alerts. In 2 cases, an intraoperative wake-up test was negative and in 3 cases, surgery was completed without a wake-up test and without recovery of TcMEP signals. No new postoperative neurologic deficits were observed in these patients. One patient with new postoperative weakness was correctly predicted by loss of TcMEP signals. No new deficit was observed in the remaining 46 patients. Statistical analysis revealed significantly higher body mass index (28.8 vs. 35.0; P = 0.032) and length of surgery (191 vs. 283 minutes; P = 0.019) in patients with false positive alerts. CONCLUSION: In this series of cervical myelopathy patients, sensitivity and specificity of TcMEP for detection of clinically significant intraoperative cord injury were 100% and 90%, respectively. Sensitivity and specificity of SSEP were 0% and 100%, respectively. The positive predictive value of a TcMEP alert was 17%. Possible risk factors for false positive TcMEP alerts include obesity and increased length of surgery. This study supports superior sensitivity of TcMEP compared with SSEP monitoring but identifies a relatively high false positive rate even in a selected high-risk cervical myelopathy population when this modality is applied in practice.

A comparison of long-term outcomes of translaminar facet screw fixation and pedicle screw fixation: a prospective study.

OBJECT: In this paper, the authors compare the long-term outcomes of translaminar facet screw fixation (TFSF) and pedicle screw fixation (PSF) in the treatment of degenerative lumbosacral disease. METHODS: This prospective analytical study was performed to compare the long-term outcomes of TFSF and PSF for degenerative lumbosacral disease. Outcomes were defined as the need for reoperation for the development of a nonunion, end-fusion degeneration, or for explantation of hardware. RESULTS: A total of 77 patients were analyzed. Thirty-seven patients underwent PSF and 40 received TFSF. Twenty-three of the 77 patients required a reoperation: 13 (32.5%) of the 40 patients in the TFSF group and 10 (27%) of the 37 the patients in the PSF group. The overall mean time to reoperation (regardless of outcome) was 4.05 years. For patients in the TFSF group the mean time to reoperation was 2.94 years, whereas it was 4.35 years in the PSF group (p = 0.34). Nonunion was noted in seven of the 40 patients in the TFSF group and one of 37 in the PSF group. The mean time to surgery for nonunion for patients in the TFSF group was 3.46 years and for those in the PSF group it was 6.27 years (p = 0.04). Surgery for end-fusion degeneration was performed in two patients in the TFSF group and five in the PSF group (p = 0.43). Explantation of hardware was performed in two patients with TFSF and four patients with PSF. Multivariable analysis revealed a statistically significant difference in the time to surgery for nonunion between PSF and TFSF (p = 0.048), with a hazard ratio of 0.097 (95% confidence interval 0.01-0.98). CONCLUSIONS: Findings from the current prospective study suggest that there is an increased risk of requirement for a reoperation for nonunion among TFSF cases compared with PSF cases.

Occipitocondylar hyperplasia: an unusual craniovertebral junction anomaly causing myelopathy. Case report.

The authors of this brief case report describe a previously unreported developmental variant of the craniovertebral junction. A 10-year-old girl who presented with cervical myelopathy was found to have cervicomedullary compression by hypertrophic occipital condyles. Decompression was achieved via a midline dorsal approach with no complications. The embryology of this area is briefly reviewed to attempt to explain the origin of this anomaly.