Publications by authors named "James D Guest"

41 Publications

Deep brain stimulation of midbrain locomotor circuits in the freely moving pig.

Brain Stimul 2021 Feb 27;14(3):467-476. Epub 2021 Feb 27.

Neuroscience Graduate Program, University of Miami Miller School of Medicine, Miami, FL, USA; The Miami Project to Cure Paralysis, University of Miami Miller School of Medicine, Miami, FL, USA; Department of Neurological Surgery, University of Miami Miller School of Medicine, Miami, FL, USA. Electronic address:

Background: Deep brain stimulation (DBS) of the mesencephalic locomotor region (MLR) has been studied as a therapeutic target in rodent models of stroke, parkinsonism, and spinal cord injury. Clinical DBS trials have targeted the closely related pedunculopontine nucleus in patients with Parkinson's disease as a therapy for gait dysfunction, with mixed reported outcomes. Recent studies suggest that optimizing the MLR target could improve its effectiveness.

Objective: We sought to determine if stereotaxic targeting and DBS in the midbrain of the pig, in a region anatomically similar to that previously identified as the MLR in other species, could initiate and modulate ongoing locomotion, as a step towards generating a large animal neuromodulation model of gait.

Methods: We implanted Medtronic 3389 electrodes into putative MLR structures in Yucatan micropigs to characterize the locomotor effects of acute DBS in this region, using EMG recordings, joint kinematics, and speed measurements on a manual treadmill.

Results: MLR DBS initiated and augmented locomotion in freely moving micropigs. Effective locomotor sites centered around the cuneiform nucleus and stimulation frequency controlled locomotor speed and stepping frequency. Off-target stimulation evoked defensive and aversive behaviors that precluded locomotion in the animals.

Conclusion: Pigs appear to have an MLR and can be used to model neuromodulation of this gait-promoting center. These results indicate that the pig is a useful model to guide future clinical studies for optimizing MLR DBS in cases of gait deficiencies associated with such conditions as Parkinson's disease, spinal cord injury, or stroke.
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http://dx.doi.org/10.1016/j.brs.2021.02.017DOI Listing
February 2021

Neurophysiological Changes in the First Year After Cell Transplantation in Sub-acute Complete Paraplegia.

Front Neurol 2020 18;11:514181. Epub 2021 Jan 18.

The Miami Project to Cure Paralysis, Miller School of Medicine, The University of Miami, Miami, FL, United States.

Neurophysiological testing can provide quantitative information about motor, sensory, and autonomic system connectivity following spinal cord injury (SCI). The clinical examination may be insufficiently sensitive and specific to reveal evolving changes in neural circuits after severe injury. Neurophysiologic data may provide otherwise imperceptible circuit information that has rarely been acquired in biologics clinical trials in SCI. We reported a Phase 1 study of autologous purified Schwann cell suspension transplantation into the injury epicenter of participants with complete subacute thoracic SCI, observing no clinical improvements. Here, we report longitudinal electrophysiological assessments conducted during the trial. Six participants underwent neurophysiology screening pre-transplantation with three post-transplantation neurophysiological assessments, focused on the thoracoabdominal region and lower limbs, including MEPs, SSEPs, voluntarily triggered EMG, and changes in GSR. We found several notable signals not detectable by clinical exam. In all six participants, thoracoabdominal motor connectivity was detected below the clinically assigned neurological level defined by sensory preservation. Additionally, small voluntary activations of leg and foot muscles or positive lower extremity MEPs were detected in all participants. Voluntary EMG was most sensitive to detect leg motor function. The recorded MEP amplitudes and latencies indicated a more caudal thoracic level above which amplitude recovery over time was observed. In contrast, further below, amplitudes showed less improvement, and latencies were increased. Intercostal spasms observed with EMG may also indicate this thoracic "motor level." Galvanic skin testing revealed autonomic dysfunction in the hands above the injury levels. As an open-label study, we can establish no clear link between these observations and cell transplantation. This neurophysiological characterization may be of value to detect therapeutic effects in future controlled studies.
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http://dx.doi.org/10.3389/fneur.2020.514181DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7848788PMC
January 2021

Indicators of Quality of Care in Individuals With Traumatic Spinal Cord Injury: A Scoping Review.

Global Spine J 2021 Jan 25:2192568220981988. Epub 2021 Jan 25.

Sina Trauma and Surgery Research Center, Tehran University of Medical Sciences, Tehran, Iran.

Study Design: Scoping review.

Objectives: To identify a practical and reproducible approach to organize Quality of Care Indicators (QoCI) in individuals with traumatic spinal cord injury (TSCI).

Methods: A comprehensive literature review was conducted in the Cochrane Central Register of Controlled Trials (CENTRAL) (Date: May 2018), MEDLINE (1946 to May 2018), and EMBASE (1974 to May 2018). Two independent reviewers screened 6092 records and included 262 full texts, among which 60 studies were included for qualitative analysis. We included studies, with no language restriction, containing at least 1 quality of care indicator for individuals with traumatic spinal cord injury. Each potential indicator was evaluated in an online, focused group discussion to define its categorization (healthcare system structure, medical process, and individuals with Traumatic Spinal Cord Injury related outcomes), definition, survey options, and scale.

Results: A total of 87 indicators were identified from 60 studies screened using our eligibility criteria. We defined each indicator. Out of 87 indicators, 37 appraised the healthcare system structure, 30 evaluated medical processes, and 20 included individuals with TSCI related outcomes. The healthcare system structure included the impact of the cost of hospitalization and rehabilitation, as well as staff and patient perception of treatment. The medical processes included targeting physical activities for improvement of health-related outcomes and complications. Changes in motor score, functional independence, and readmission rates were reported as individuals with TSCI-related outcomes indicators.

Conclusion: Indicators of quality of care in the management of individuals with TSCI are important for health policy strategists to standardize healthcare assessment, for clinicians to improve care, and for data collection efforts including registries.
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http://dx.doi.org/10.1177/2192568220981988DOI Listing
January 2021

Population Averaged Stereotaxic T2w MRI Brain Template for the Adult Yucatan Micropig.

Front Neuroanat 2020 13;14:599701. Epub 2020 Nov 13.

Neuroscience Graduate Program, University of Miami Miller School of Medicine, Miami, FL, United States.

Population averaged brain templates are an essential tool for imaging-based neuroscience research, providing investigators with information about the expected size and morphology of brain structures and the spatial relationships between them, within a demographic cross-section. This allows for a standardized comparison of neuroimaging data between subjects and provides neuroimaging software with a probabilistic framework upon which further processing and analysis can be based. Many different templates have been created to represent specific study populations and made publicly available for human and animal research. An increasingly studied animal model in the neurosciences that still lacks appropriate brain templates is the adult Yucatan micropig. In particular, T2-weighted templates are absent in this species as a whole. To address this need and provide a tool for neuroscientists wishing to pursue neuroimaging research in the adult micropig, we present the construction of population averaged ( = 16) T2-weighted MRI brain template for the adult Yucatan micropig. Additionally, we present initial analysis of T1-weighted ( = 3), and diffusion-weighted ( = 3) images through multimodal registration of these contrasts to our T2 template. The strategies used here may also be generalized to create similar templates for other study populations or species in need of template construction.
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http://dx.doi.org/10.3389/fnana.2020.599701DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7691581PMC
November 2020

Dissecting Brainstem Locomotor Circuits: Converging Evidence for Cuneiform Nucleus Stimulation.

Front Syst Neurosci 2020 21;14:64. Epub 2020 Aug 21.

Neuroscience Graduate Program, University of Miami Miller School of Medicine, Miami, FL, United States.

There are a pressing and unmet need for effective therapies for freezing of gait (FOG) and other neurological gait disorders. Deep brain stimulation (DBS) of a midbrain target known as the pedunculopontine nucleus (PPN) was proposed as a potential treatment based on its postulated involvement in locomotor control as part of the mesencephalic locomotor region (MLR). However, DBS trials fell short of expectations, leading many clinicians to abandon this strategy. Here, we discuss the potential reasons for this failure and review recent clinical data along with preclinical optogenetics evidence to argue that another nearby nucleus, the cuneiform nucleus (CnF), may be a superior target.
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http://dx.doi.org/10.3389/fnsys.2020.00064DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7473103PMC
August 2020

Adaptive trial designs for spinal cord injury clinical trials directed to the central nervous system.

Spinal Cord 2020 Dec 16;58(12):1235-1248. Epub 2020 Sep 16.

International Collaboration on Repair Discoveries, University of British Columbia, Vancouver, BC, Canada.

Study Design: Narrative review.

Purpose: To provide an overview of adaptive trial designs, and describe how adaptive methods can address persistent challenges encountered by randomized controlled trials of people with spinal cord injury (SCI).

Results: With few exceptions, adaptive methodologies have not been incorporated into clinical trial designs of people with SCI. Adaptive methods provide an opportunity to address high study costs, slow recruitment, and excessive amount of time needed to carry out the trial. The availability of existing SCI registries are well poised to support modeling and simulation, both of which are used extensively in adaptive trial designs. Eight initiatives for immediate advancement of adaptive methods in SCI were identified.

Conclusion: Although successfully applied in other fields, adaptive clinical trial designs in SCI clinical trial programs have been narrow in scope and few in number. Immediate application of several adaptive methods offers opportunity to improve efficiency of SCI trials. Concerted effort is needed by all stakeholders to advance adaptive clinical trial design methodology in SCI.
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http://dx.doi.org/10.1038/s41393-020-00547-8DOI Listing
December 2020

Natural history of neurological improvement following complete (AIS A) thoracic spinal cord injury across three registries to guide acute clinical trial design and interpretation.

Spinal Cord 2019 Sep 10;57(9):753-762. Epub 2019 Jun 10.

Department of Neurosurgery, University of Miami, Miami, FL, USA.

Study Design: Retrospective, longitudinal analysis of motor and sensory outcomes following thoracic (T2-T12) sensorimotor complete spinal cord injury (SCI) in selected patients enrolled into three SCI) registries.

Objectives: To establish a modern-day international benchmark for neurological recovery following traumatic complete thoracic sensorimotor SCI in a population similar to those enrolled in acute clinical trials.

Setting: Affiliates of the North American Clinical Trial Network (NACTN), European Multicenter Study about Spinal Cord Injury (EMSCI), and the Spinal Cord Injury Model Systems (SCIMS).

Methods: Only traumatic thoracic injured patients between 2006 and 2016 meeting commonly used clinical trial inclusion/exclusion criteria such as: age 16-70, T2-T12 neurological level of injury (NLI), ASIA Impairment Scale (AIS) A, non-penetrating injury, acute neurological exam within 7 days of injury, and follow-up neurological exam at least ~ 6 months post injury, were included in this analysis. International Standards for Neurological Classification of Spinal Cord injury outcomes including AIS conversion rate, NLI, and sensory and motor scores/levels were compiled.

Results: A total of 170 patients were included from the three registries: 12 from NACTN, 64 from EMSCI, and 94 from SCIMS. AIS conversion rates at approximately 6 months post injury varied from 16.7% to 23.4% (21.1% weighted average). Improved conversion rates were observed in all registries for low thoracic (T10-T12) injuries when compared with high/mid thoracic (T2-T9) injuries. The NLI was generally stable and lower extremity motor score (LEMS) improvement was uncommon and usually limited to low thoracic injuries only.

Conclusions: This study presents the aggregation of selected multinational natural history recovery data in thoracic AIS A patients from three SCI registries and demonstrates comparable minimal improvement of ISNCSCI-scored motor and sensory function following these injuries, whereas conversions to higher AIS grades occur at a frequency of ~20%. These data inform the development of future clinical trial protocols in this important patient population for the interpretation of the safety and potential clinical benefit of new therapies, and the potential applicability in a multinational setting.

Sponsorship: InVivo Therapeutics.
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http://dx.doi.org/10.1038/s41393-019-0299-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6760562PMC
September 2019

The challenge of recruitment for neurotherapeutic clinical trials in spinal cord injury.

Spinal Cord 2019 May 8;57(5):348-359. Epub 2019 Apr 8.

ICORD, University of British Columbia, Vancouver, Canada.

Study Design: Narrative review by individuals experienced in the recruitment of participants to neurotherapeutic clinical trials in spinal cord injury (SCI).

Objectives: To identify key problems of recruitment and explore potential approaches to overcoming them.

Methods: Published quantitative experience with recruitment of large-scale, experimental neurotherapeutic clinical studies targeting central nervous system and using primary outcome assessments validated for SCI over the last 3 decades was summarized. Based on this experience, potential approaches to improving recruitment were elicited from the authors.

Results: The rate of recruitment has varied between studies, depending on protocol design and other factors, but particularly inclusion/exclusion criteria. The recruitment rate also ranged over an order of magnitude between individual centers in a given study. In older multicenter studies, average recruitment rate was approximately one person per study center per month. More recent trials experienced lower rates of recruitment and potential reasons for this trend were examined. The current roles and potential of various stakeholder organizations in addressing problems of recruitment were explored. In addition, recent developments in methodology may help reduce the number of subjects required for well-powered studies.

Conclusions: Several approaches are emerging to improve clinical trial design, efficacy outcome measures, and quantifiable surrogate markers, all of which should reduce the number of participants required for adequate statistical power. There is a growing sense of cooperation between various stakeholders but more should be done to bring together consumer and provider groups to improve recruitment and the effectiveness and relevance of neurotherapeutic clinical trials.
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http://dx.doi.org/10.1038/s41393-019-0276-2DOI Listing
May 2019

Imaging characteristics of chronic spinal cord injury identified during screening for a cell transplantation clinical trial.

Neurosurg Focus 2019 03;46(3):E8

Departments of1Neurological Surgery.

OBJECTIVEIn cell transplantation trials for spinal cord injury (SCI), quantifiable imaging criteria that serve as inclusion criteria are important in trial design. The authors' institutional experience has demonstrated an overall high rate of screen failures. The authors examined the causes for trial exclusion in a phase I, open-lab clinical trial examining the role of autologous Schwann cell intramedullary transplantation. Specifically, they reviewed the imaging characteristics in people with chronic SCI that excluded applicants from the trial, as this was a common cause of screening failures in their study.METHODSThe authors reviewed MRI records from 152 people with chronic (> 1 year) SCI who volunteered for intralesional Schwann cell transplantation but were deemed ineligible by prospectively defined criteria. Rostral-caudal injury lesion length was measured along the long axis of the spinal cord in the sagittal plane on T2-weighted MRI. Other lesion characteristics, specifically those pertaining to lesion cavity structure resulting in trial exclusion, were recorded.RESULTSImaging records from 152 potential participants with chronic SCI were reviewed, 42 with thoracic-level SCI and 110 with cervical-level SCI. Twenty-three individuals (55%) with thoracic SCI and 70 (64%) with cervical SCI were not enrolled in the trial based on imaging characteristics. For potential participants with thoracic injuries who did not meet the screening criteria for enrollment, the average rostral-caudal sagittal lesion length was 50 mm (SD 41 mm). In applicants with cervical injuries who did not meet the screening criteria for enrollment, the average sagittal lesion length was 34 mm (SD 21 mm).CONCLUSIONSWhile screening people with SCI for participation in a cell transplantation clinical trial, lesion length or volume can exclude potential subjects who appear appropriate candidates based on neurological eligibility criteria. In planning future cell-based therapy trials, the limitations incurred by lesion size should be considered early due to the screening burden and impact on candidate selection.
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http://dx.doi.org/10.3171/2018.12.FOCUS18593DOI Listing
March 2019

Dichotomous Locomotor Recoveries Are Predicted by Acute Changes in Segmental Blood Flow after Thoracic Spinal Contusion Injuries in Pigs.

J Neurotrauma 2019 05 20;36(9):1399-1415. Epub 2018 Nov 20.

1 The Miami Project to Cure Paralysis, University of Miami, Miller School of Medicine, Miami, Florida.

Neuroimaging facilitates the translation of animal pre-clinical research to human application. The large porcine spinal cord is useful for testing invasive interventions. Ideally, the safety and efficacy of a delayed intervention is tested in pigs that have recovered sufficiently after spinal cord injury (SCI) to allow either deterioration or improvement of function to be detected. We set out to create moderate severity T9 injuries in Yucatan minipigs by conducting a bridging study adapting methods previously developed in infant piglets. The injury severity was varied according to two pneumatic impactor parameters: the piston compression depth into tissue or the velocity. To stratify locomotor recovery, a 10-point scale used in prior piglet studies was redefined through longitudinal observations of spontaneous recovery. Using hindlimb body weight support to discriminate injury severity, we found that end-point recovery was strongly bimodal to either non-weight-bearing plegia with reciprocating leg movements (<5/10) or recovery of weight bearing that improved toward a ceiling effect (≥ 8/10). No intermediate recovery animals were observed at 2 months post-injury. The ability of intra-operative ultrasound and acute magnetic resonance imaging (MRI) to provide immediate predictive feedback regarding tissue and vascular changes following SCI was assessed. There was an inverse association between locomotor outcome and early gray matter hemorrhage on MRI and ultrasound. Epicenter blood flow following contusion predicted recovery or non-recovery of weight-bearing. The depth of the dorsal cerebrospinal fluid space, which varied between animals, influenced injury severity and confounded the results in this fixed-stroke paradigm.
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http://dx.doi.org/10.1089/neu.2018.6087DOI Listing
May 2019

Internal decompression of the acutely contused spinal cord: Differential effects of irrigation only versus biodegradable scaffold implantation.

Biomaterials 2018 12 19;185:284-300. Epub 2018 Sep 19.

InVivo Therapeutics Corporation, Cambridge, MA, USA. Electronic address:

Severe spinal cord injury leads to hemorrhage, edema and elevated tissue pressures that propagate ischemia. Liquefactive necrosis of damaged tissue eventually results in chronic cavities due to a wound healing process lacking adhesive contractile cells. Biomaterials can potently influence wound healing responses. Internal decompression (ID) refers to pial opening, allowing spontaneous extrusion and irrigation of fluid necrotic debris relieving pressure and resulting in a space for biomaterial scaffold insertion. After thoracic contusions, rats were randomized to: contusion only, contusion + ID and contusion + ID + PLGA-PLL scaffold implantation, to test for neuroprotection and endogenous repair over 3 months. ID alone reduced inflammatory activity, cavity volume, and increased tissue sparing. Scaffold biodegradation produced delayed ingrowth of inflammatory and other cells resulting in endogenously derived laminin-rich tissue, marked reduction in cavitation and presence of tissue remodeling macrophages. Extensive recruitment of Schwann cells into adjacent spared white matter occurred, greatest in scaffold-implanted animals. Despite tissue preservation with myelin repair, no groups differed significantly in open field locomotion. However, across all rats, spared epicenter tissue and locomotor outcomes were correlated. Scaffold-implanted animals showed no obvious toxicity. To study the clinical feasibility, timing and indications for scaffold implantation, Göttingen minipigs underwent ID and were implanted with scaffolds 4, 6, and 24 h after T10 contusion. High intra-spinal tissue pressures fell to pre-injury levels after ID and scaffold implantation. Extrusion of necrotic debris left sufficient space for a sized scaffold. These results provided the preclinical rationale for a current clinical study of biomaterial scaffold implantation into the human injured spinal cord.
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http://dx.doi.org/10.1016/j.biomaterials.2018.09.025DOI Listing
December 2018

Method and Apparatus for the Automated Delivery of Continuous Neural Stem Cell Trails Into the Spinal Cord of Small and Large Animals.

Neurosurgery 2019 10;85(4):560-573

The Miami Project to Cure Paralysis, University of Miami, Miami, Florida.

Background: Immature neurons can extend processes after transplantation in adult animals. Neuronal relays can form between injected neural stem cells (NSCs) and surviving neurons, possibly improving recovery after spinal cord injury (SCI). Cell delivery methods of single or multiple bolus injections of concentrated cell suspensions thus far tested in preclinical and clinical experiments are suboptimal for new tract formation. Nonuniform injectate dispersal is often seen due to gravitational cell settling and clumping. Multiple injections have additive risks of hemorrhage, parenchymal damage, and cellular reflux and require additional surgical exposure. The deposition of multiply delivered cells boluses may be uneven and discontinuous.

Objective: To develop an injection apparatus and methodology to deliver continuous cellular trails bridging spinal cord lesions.

Methods: We improved the uniformity of cellular trails by formulating NSCs in hyaluronic acid. The TrailmakerTM stereotaxic injection device was automatized to extend a shape memory needle from a single-entry point in the spinal cord longitudinal axis to "pioneer" a new trail space and then retract while depositing an hyaluronic acid-NSC suspension. We conducted testing in a collagen spinal models, and animal testing using human NSCs (hNSCs) in rats and minipigs.

Results: Continuous surviving trails of hNSCs within rat and minipig naive spinal cords were 12 and 40 mm in length. hNSC trails were delivered across semi-acute contusion injuries in rats. Transplanted hNSCs survived and were able to differentiate into neural lineage cells and astrocytes.

Conclusion: The TrailmakerTM creates longitudinal cellular trails spanning multiple levels from a single-entry point. This may enhance the ability of therapeutics to promote functional relays after SCI.
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http://dx.doi.org/10.1093/neuros/nyy379DOI Listing
October 2019

Clinical and Neurophysiological Changes after Targeted Intrathecal Injections of Bone Marrow Stem Cells in a C3 Tetraplegic Subject.

J Neurotrauma 2019 02 23;36(3):500-516. Epub 2018 Jul 23.

1 The Miami Project to Cure Paralysis, University of Miami, Miller School of Medicine, Miami, Florida.

High-level quadriplegia is a devastating condition with limited treatment options. Bone marrow derived stem cells (BMSCs) are reported to have immunomodulatory and neurotrophic effects in spinal cord injury (SCI). We report a subject with complete C2 SCI who received three anatomically targeted intrathecal infusions of BMSCs under a single-patient expanded access investigational new drug (IND). She underwent intensive physical therapy and was followed for >2 years. At end-point, her American Spinal Injury Association Impairment Scale (AIS) grade improved from A to B, and she recovered focal pressure touch sensation over several body areas. We conducted serial neurophysiological testing to monitor changes in residual connectivity. Motor, sensory, and autonomic system testing included motor evoked potentials (MEPs), somatosensory evoked potentials (SSEPs), electromyography (EMG) recordings, F waves, galvanic skin responses, and tilt-table responses. The quality and magnitude of voluntary EMG activations increased over time, but remained below the threshold of clinically obvious movement. Unexpectedly, at 14 months post-injury, deep inspiratory maneuvers triggered respiratory-like EMG bursting in the biceps and several other muscles. This finding means that connections between respiratory neurons and motor neurons were newly established, or unmasked. We also report serial analysis of MRI, International Standards for Neurological Classification of SCI (ISNCSCI), pulmonary function, pain scores, cerebrospinal fluid (CSF) cytokines, and bladder assessment. As a single case, the linkage of the clinical and neurophysiological changes to either natural history or to the BMSC infusions cannot be resolved. Nevertheless, such detailed neurophysiological assessment of high cervical SCI patients is rarely performed. Our findings indicate that electrophysiology studies are sensitive to define both residual connectivity and new plasticity.
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http://dx.doi.org/10.1089/neu.2018.5716DOI Listing
February 2019

Natural History, Predictors of Outcome, and Effects of Treatment in Thoracic Spinal Cord Injury: A Multi-Center Cohort Study from the North American Clinical Trials Network.

J Neurotrauma 2018 11 7;35(21):2554-2560. Epub 2018 Jun 7.

8 Division of Neurosurgery, Toronto Western Hospital, University of Toronto , Toronto, Ontario, Canada .

The course, treatment response, and recovery potential after acute traumatic spinal cord injury (SCI) have been shown to differ depending on the neurological level of injury. There are limited data focused on thoracic-level injuries, however. A cohort of 86 patients from the prospectively maintained North American Clinical Trials Network SCI registry were identified and studied to characterize the patterns of neurological recovery and to determine rates of acute hospital death and pulmonary complications. Regression analyses were used to examine the relationship between timing of surgery and administration of methylprednisolone on neurologic and clinical outcomes. Neurological conversion (≥1 American Spinal Injury Association Impairment Scale [AIS] grade improvement) was poorest for AIS grade A patients; 14.3% converted at last available follow-up (mean eight months). While rates of conversion were more optimistic for AIS-B patients (54.5%) and AIS C injuries (77.8%) at the same time point, none of the AIS grade D patients converted to AIS E. At last available follow-up (mean eight months), the magnitudes of lower motor extremity score (LEMS) change were highest for AIS C injuries (21.9 points), then AIS B (17.7 points), AIS D (16.4 points), and finally AIS A (2.5 points) (p < 0.05). Early surgical intervention (<24 h post-injury) was independently associated with an additional seven points in motor recovery and a 60% decreased incidence of pulmonary events (p < 0.05). Methylprednisolone administration was not an independent predictor of neurological outcome or pulmonary complications. Evaluation of this cohort obtained from a modern multi-center SCI registry provides an update on the natural history, acute death, and incidence of pulmonary complications after traumatic thoracic SCI. Although small sample size limited the extent of analyses possible, early surgical treatment was associated with significantly larger motor recovery and lower rates of pulmonary complications.
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http://dx.doi.org/10.1089/neu.2017.5535DOI Listing
November 2018

Intraspinal Delivery of Schwann Cells for Spinal Cord Injury.

Methods Mol Biol 2018 ;1739:467-484

The Miami Project to Cure Paralysis, University of Miami, Miller School of Medicine, Miami, FL, USA.

Cell transplant-mediated tissue repair of the damaged spinal cord is being tested in several clinical trials. The current candidates are neural stem cells, stromal cells, and autologous Schwann cells (aSC). Due to their peripheral origin and limited penetration of astrocytic regions, aSC are transplanted intralesionally as compared to neural stem cells that are transplanted into intact spinal cord. Injections into either location can cause iatrogenic injury, and thus technical precision is important in the therapeutic risk-benefit equation. In this chapter, we discuss how we bridged from transplant studies in large animals to human application for two Phase 1 aSC transplant studies, one subacute and one chronic. Preclinical SC transplant studies conducted at the University of Miami in 2009-2012 in rodents, minipigs, and primates supported a successful Investigational New Drug (IND) submission for a Phase 1 trial in subacute complete spinal cord injury (SCI). Our studies optimized the safety and efficiency of intralesional cell delivery for subacute human SCI and led to the development of new simpler techniques for cell delivery into subjects with chronic SCI. Key parameters of delivery methodology include precision localization of the injury site, stereotaxic devices to control needle trajectory, method of entry into the spinal cord, spinal cord motion reduction, the volume and density of the cell suspension, rate of delivery, and control of shear stresses on cells.
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http://dx.doi.org/10.1007/978-1-4939-7649-2_31DOI Listing
January 2019

Considerations and recommendations for selection and utilization of upper extremity clinical outcome assessments in human spinal cord injury trials.

Spinal Cord 2018 05 28;56(5):414-425. Epub 2017 Dec 28.

University of British Columbia, Vancouver, Canada.

Study Design: This is a focused review article.

Objectives: This review presents important features of clinical outcomes assessments (COAs) in human spinal cord injury research. Considerations for COAs by trial phase and International Classification of Functioning, Disability and Health are presented as well as strengths and recommendations for upper extremity COAs for research. Clinical trial tools and designs to address recruitment challenges are identified.

Methods: The methods include a summary of topics discussed during a two-day workshop, conceptual discussion of upper extremity COAs and additional focused literature review.

Results: COAs must be appropriate to trial phase and particularly in mid-late-phase trials, should reflect recovery vs. compensation, as well as being clinically meaningful. The impact and extent of upper vs. lower motoneuron disease should be considered, as this may affect how an individual may respond to a given therapeutic. For trials with broad inclusion criteria, the content of COAs should cover all severities and levels of SCI. Specific measures to assess upper extremity function as well as more comprehensive COAs are under development. In addition to appropriate use of COAs, methods to increase recruitment, such as adaptive trial designs and prognostic modeling to prospectively stratify heterogeneous populations into appropriate cohorts should be considered.

Conclusions: With an increasing number of clinical trials focusing on improving upper extremity function, it is essential to consider a range of factors when choosing a COA.

Sponsors: Craig H. Neilsen Foundation, Spinal Cord Outcomes Partnership Endeavor.
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http://dx.doi.org/10.1038/s41393-017-0015-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5951792PMC
May 2018

Human Schwann cells exhibit long-term cell survival, are not tumorigenic and promote repair when transplanted into the contused spinal cord.

Glia 2017 08 22;65(8):1278-1301. Epub 2017 May 22.

The Miami Project to Cure Paralysis, The Department of Neurological Surgery, The University of Miami Miller School of Medicine, Miami, Florida, 33136.

The transplantation of rodent Schwann cells (SCs) provides anatomical and functional restitution in a variety of spinal cord injury (SCI) models, supporting the recent translation of SCs to phase 1 clinical trials for human SCI. Whereas human (Hu)SCs have been examined experimentally in a complete SCI transection paradigm, to date the reported behavior of SCs when transplanted after a clinically relevant contusive SCI has been restricted to the use of rodent SCs. Here, in a xenotransplant, contusive SCI paradigm, the survival, biodistribution, proliferation and tumorgenicity as well as host responses to HuSCs, cultured according to a protocol analogous to that developed for clinical application, were investigated. HuSCs persisted within the contused nude rat spinal cord through 6 months after transplantation (longest time examined), exhibited low cell proliferation, displayed no evidence of tumorigenicity and showed a restricted biodistribution to the lesion. Neuropathological examination of the CNS revealed no adverse effects of HuSCs. Animals exhibiting higher numbers of surviving HuSCs within the lesion showed greater volumes of preserved white matter and host rat SC and astrocyte ingress as well as axon ingrowth and myelination. These results demonstrate the safety of HuSCs when employed in a clinically relevant experimental SCI paradigm. Further, signs of a potentially positive influence of HuSC transplants on host tissue pathology were observed. These findings show that HuSCs exhibit a favorable toxicity profile for up to 6 months after transplantation into the contused rat spinal cord, an important outcome for FDA consideration of their use in human clinical trials.
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http://dx.doi.org/10.1002/glia.23161DOI Listing
August 2017

Safety of Autologous Human Schwann Cell Transplantation in Subacute Thoracic Spinal Cord Injury.

J Neurotrauma 2017 11 21;34(21):2950-2963. Epub 2017 Mar 21.

1 The Miami Project to Cure Paralysis, The University of Miami Miller School of Medicine , Miami, Florida.

The rationale for implantation of autologous human Schwann cells (SCs) in persons with subacute spinal cord injury (SCI) is based on evidence that transplanted SCs are neuroprotective, support local axonal plasticity, and are capable of myelinating axons. A Phase I clinical trial was conducted to evaluate the safety of autologous human SC transplantation into the injury epicenter of six subjects with subacute SCI. The trial was an open-label, unblinded, non-randomized, non-placebo controlled study with a dose escalation design and standard medical rehabilitation. Participants were paraplegics with neurologically complete, trauma-induced spinal lesions. Autologous SCs were cultured in vitro from a sural nerve harvested from each participant and injected into the epicenter of the spinal lesion. Outcome measures for safety were protocol compliance, feasibility, adverse events, stability of neurological level, absence of detectable mass lesion, and the emergence of clinically significant neuropathic pain or muscle spasticity no greater than expected for a natural course cohort. One year post-transplantation, there were no surgical, medical, or neurological complications to indicate that the timing or procedure for the cell transplantation was unsafe. There were no adverse events or serious adverse events related to the cell therapy. There was no evidence of additional spinal cord damage, mass lesion, or syrinx formation. We conclude that it is feasible to identify eligible candidates, appropriately obtain informed consent, perform a peripheral nerve harvest to obtain SCs within 5-30 days of injury, and perform an intra-spinal transplantation of highly purified autologous SCs within 4-7 weeks of injury.
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http://dx.doi.org/10.1089/neu.2016.4895DOI Listing
November 2017

Characterization of Motor and Somatosensory Evoked Potentials in the Yucatan Micropig Using Transcranial and Epidural Stimulation.

J Neurotrauma 2017 09 28;34(18):2595-2608. Epub 2016 Nov 28.

1 The Miami Project to Cure Paralysis, University of Miami , Miller School of Medicine, Miami, Florida.

Yucatan micropigs have brain and spinal cord dimensions similar to humans and are useful for certain spinal cord injury (SCI) translational studies. Micropigs are readily trained in behavioral tasks, allowing consistent testing of locomotor loss and recovery. However, there has been little description of their motor and sensory pathway neurophysiology. We established methods to assess motor and sensory cortical evoked potentials in the anesthetized, uninjured state. We also evaluated epidurally evoked motor and sensory stimuli from the T6 and T9 levels, spanning the intended contusion injury epicenter. Response detection frequency, mean latency and amplitude values, and variability of evoked potentials were determined. Somatosensory evoked potentials were reliable and best detected during stimulation of peripheral nerve and epidural stimulation by referencing the lateral cortex to midline Fz. The most reliable hindlimb motor evoked potential (MEP) occurred in tibialis anterior. We found MEPs in forelimb muscles in response to thoracic epidural stimulation likely generated from propriospinal pathways. Cranially stimulated MEPs were easier to evoke in the upper limbs than in the hindlimbs. Autopsy studies revealed substantial variations in cortical morphology between animals. This electrophysiological study establishes that neurophysiological measures can be reliably obtained in micropigs in a time frame compatible with other experimental procedures, such as SCI and transplantation. It underscores the need to better understand the motor control pathways, including the corticospinal tract, to determine which therapeutics are suitable for testing in the pig model.
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http://dx.doi.org/10.1089/neu.2016.4511DOI Listing
September 2017

Large animal and primate models of spinal cord injury for the testing of novel therapies.

Exp Neurol 2015 Jul 19;269:154-68. Epub 2015 Apr 19.

University of British Columbia, ICORD, Room 6196, Blusson Spinal Cord Centre, 818 West 10th Avenue, Vancouver, BC V5Z 1 M9, Canada. Electronic address:

Large animal and primate models of spinal cord injury (SCI) are being increasingly utilized for the testing of novel therapies. While these represent intermediary animal species between rodents and humans and offer the opportunity to pose unique research questions prior to clinical trials, the role that such large animal and primate models should play in the translational pipeline is unclear. In this initiative we engaged members of the SCI research community in a questionnaire and round-table focus group discussion around the use of such models. Forty-one SCI researchers from academia, industry, and granting agencies were asked to complete a questionnaire about their opinion regarding the use of large animal and primate models in the context of testing novel therapeutics. The questions centered around how large animal and primate models of SCI would be best utilized in the spectrum of preclinical testing, and how much testing in rodent models was warranted before employing these models. Further questions were posed at a focus group meeting attended by the respondents. The group generally felt that large animal and primate models of SCI serve a potentially useful role in the translational pipeline for novel therapies, and that the rational use of these models would depend on the type of therapy and specific research question being addressed. While testing within these models should not be mandatory, the detection of beneficial effects using these models lends additional support for translating a therapy to humans. These models provides an opportunity to evaluate and refine surgical procedures prior to use in humans, and safety and bio-distribution in a spinal cord more similar in size and anatomy to that of humans. Our results reveal that while many feel that these models are valuable in the testing of novel therapies, important questions remain unanswered about how they should be used and how data derived from them should be interpreted.
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http://dx.doi.org/10.1016/j.expneurol.2015.04.008DOI Listing
July 2015

A prospective, multicenter, phase I matched-comparison group trial of safety, pharmacokinetics, and preliminary efficacy of riluzole in patients with traumatic spinal cord injury.

J Neurotrauma 2014 Feb 11;31(3):239-55. Epub 2013 Oct 11.

1 Houston Methodist Research Institute , Department of Neurosurgery, Houston Methodist Hospital, Houston, Texas.

A prospective, multicenter phase I trial was undertaken by the North American Clinical Trials Network (NACTN) to investigate the pharmacokinetics and safety of, as well as obtain pilot data on, the effects of riluzole on neurological outcome in acute spinal cord injury (SCI). Thirty-six patients, with ASIA impairment grades A-C (28 cervical and 8 thoracic) were enrolled at 6 NACTN sites between April 2010 and June 2011. Patients received 50 mg of riluzole PO/NG twice-daily, within 12 h of SCI, for 14 days. Peak and trough plasma concentrations were quantified on days 3 and 14. Peak plasma concentration (Cmax) and systemic exposure to riluzole varied significantly between patients. On the same dose basis, Cmax did not reach levels comparable to those in patients with amyotrophic lateral sclerosis. Riluzole plasma levels were significantly higher on day 3 than on day 14, resulting from a lower clearance and a smaller volume of distribution on day 3. Rates of medical complications, adverse events, and progression of neurological status were evaluated by comparison with matched patients in the NACTN SCI Registry. Medical complications in riluzole-treated patients occurred with incidences similar to those in patients in the comparison group. Mild-to-moderate increase in liver enzyme and bilirubin levels were found in 14-70% of patients for different enzymes. Three patients had borderline severe elevations of enzymes. No patient had elevated bilirubin on day 14 of administration of riluzole. There were no serious adverse events related to riluzole and no deaths. The mean motor score of 24 cervical injury riluzole-treated patients gained 31.2 points from admission to 90 days, compared to 15.7 points for 26 registry patients, a 15.5-point difference (p=0.021). Patients with cervical injuries treated with riluzole had more-robust conversions of impairment grades to higher grades than the comparison group.
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http://dx.doi.org/10.1089/neu.2013.2969DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3904533PMC
February 2014

Demonstrating efficacy in preclinical studies of cellular therapies for spinal cord injury - how much is enough?

Exp Neurol 2013 Oct 29;248:30-44. Epub 2013 May 29.

ICORD, University of British Columbia, Room 6196, 818 West 10th Avenue, Vancouver, BC, V5Z 1M9, Canada. Electronic address:

Cellular therapies represent a novel treatment approach for spinal cord injury (SCI), with many different cellular substrates showing promise in preclinical animal models of SCI. Considerable interest therefore exists to translate such cellular interventions into human clinical trials. Balanced against the urgency for clinical translation is the desire to establish the robustness of a cellular therapy's efficacy in preclinical studies, thereby optimizing its chances of succeeding in human trials. Uncertainty exists, however, on the extent to which a therapy needs to demonstrate efficacy in the preclinical setting in order to justify the initiation of a lengthy, expensive, and potentially risky clinical trial. The purpose of this initiative was to seek perspectives on the level of evidence required in experimental studies of cellular therapies before proceeding with clinical trials of SCI. We conducted a survey of 27 SCI researchers actively involved in either preclinical and/or clinical research of cellular interventions for SCI, and then held a focus group meeting to facilitate more in-depth discussion around a number of translational issues. These included: the use of animal models, the use of injury models and mechanisms, the window for demonstrating efficacy, independent replication, defining "relevant, meaningful efficacy" in preclinical studies, and the expectation of therapeutic benefits for cellular interventions. Here we present the key findings from both the survey and focus group meeting in order to summarize and underscore the areas of consensus and disagreement amongst the sampled researchers. It is anticipated that the knowledge generated from this initiative will help to incite future scientific discussions and expert guidelines towards translation of a cell therapy for persons with SCI.
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http://dx.doi.org/10.1016/j.expneurol.2013.05.012DOI Listing
October 2013

Evaluation of clinical experience using cell-based therapies in patients with spinal cord injury: a systematic review.

J Neurosurg Spine 2012 Sep;17(1 Suppl):230-46

Department of Neurological Surgery, Thomas Jefferson University, Philadelphia, Pennsylvania 19107, USA.

Object: Using a systematic approach, the authors evaluated the current utilization, safety, and effectiveness of cellular therapies for traumatic spinal cord injuries (SCIs) in humans.

Methods: A systematic search and critical review of the literature published through mid-January 2012 was performed. Articles included in the search were restricted to the English language, studies with at least 10 patients, and those analyzing cellular therapies for traumatic SCI. Citations were evaluated for relevance using a priori criteria, and those that met the inclusion criteria were critically reviewed. Each article was then designated a level of evidence that was developed by the Oxford Centre for Evidence-Based Medicine.

Results: The initial literature search identified 651 relevant articles, which decreased to 350 after excluding case reports and reviews. Evaluation of articles at the title/abstract level, and later at the full-text level, limited the final article set to 12 papers. The following cellular therapies employed in humans with SCI are reviewed: bone marrow mesenchymal and hematopoietic stem cells (8 studies), olfactory ensheathing cells (2 studies), Schwann cells (1 study), and fetal neurogenic tissue (1 study). Overall the quality of the literature was very low, with 3 Grade III levels of evidence and 9 Grade IV studies.

Conclusions: Several different cellular-mediated strategies for adult SCI have been reported to be relatively safe with varying degrees of neurological recovery. However, the literature is of low quality and there is a need for improved preclinical studies and prospective, controlled clinical trials.
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http://dx.doi.org/10.3171/2012.5.AOSPINE12115DOI Listing
September 2012

Riluzole for the treatment of acute traumatic spinal cord injury: rationale for and design of the NACTN Phase I clinical trial.

J Neurosurg Spine 2012 Sep;17(1 Suppl):151-6

Department of Surgery, Division of Neurosurgery and Spinal Program, University of Toronto, Toronto Western Hospital, Toronto, Ontario, Canada.

In the immediate period after traumatic spinal cord injury (SCI) a variety of secondary injury mechanisms combine to gradually expand the initial lesion size, potentially leading to diminished neurological outcomes at long-term follow-up. Riluzole, a benzothiazole drug, which has neuroprotective properties based on sodium channel blockade and mitigation of glutamatergic toxicity, is currently an approved drug that attenuates the extent of neuronal degeneration in patients with amyotrophic lateral sclerosis. Moreover, several preclinical SCI studies have associated riluzole administration with improved functional outcomes and increased neural tissue preservation. Based on these findings, riluzole has attracted considerable interest as a potential neuroprotective drug for the treatment of SCI. Currently, a Phase I trial evaluating the safety and pharmacokinetic profile of riluzole in human SCI patients is being conducted by the North American Clinical Trials Network (NACTN) for Treatment of Spinal Cord Injury. The current review summarizes the existing preclinical and clinical literature on riluzole, provides a detailed description of the Phase I trial, and suggests potential opportunities for future investigation. Clinical trial registration no.: NCT00876889.
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http://dx.doi.org/10.3171/2012.4.AOSPINE1259DOI Listing
September 2012

Incidence and severity of acute complications after spinal cord injury.

J Neurosurg Spine 2012 Sep;17(1 Suppl):119-28

Department of Neurosurgery, The Methodist Hospital, Houston, Texas 77030, USA.

Object: The aim of this multicenter, prospective study was to determine the spectrum, incidence, and severity of complications during the initial hospitalization of patients with spinal cord injury.

Methods: The study was conducted at 9 university-affiliated hospitals that comprise the clinical centers of the North American Clinical Trials Network (NACTN) for Treatment of Spinal Cord Injury. The study population comprised 315 patients admitted to NACTN clinical centers between June 25, 2005, and November 2, 2010, who had American Spinal Injury Association (ASIA) Impairment Scale grades of A-D and were 18 years of age or older. Patients were managed according to a standardized protocol.

Results: The study population was 79% male with a median age of 44 years. The leading causes of injury were falls (37%) and motor vehicle accidents (28%). The distribution of initial ASIA grades were A (40%), B (16%), C (15%), and D (29%). Fifty-eight percent of patients sustained 1 or more severe, moderate, or mild complications. Complications were associated with more severe ASIA grade: 84% of patients with Grade A and 25% of patients with Grade D had at least 1 complication. Seventy-eight percent of complications occurred within 14 days of injury. The most frequent types of severe and moderate complications were respiratory failure, pneumonia, pleural effusion, anemia, cardiac dysrhythmia, and severe bradycardia. The mortality rate was 3.5% and was associated with increased age and preexisting morbidity.

Conclusions: Knowledge of the type, frequency, time of occurrence, and severity of specific complications that occur after spinal cord injury can aid in their early detection, treatment, and prevention. The data are of importance in evaluating and selecting therapy for clinical trials.
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http://dx.doi.org/10.3171/2012.5.AOSPINE12127DOI Listing
September 2012

Predictors of pulmonary complications in blunt traumatic spinal cord injury.

J Neurosurg Spine 2012 Sep;17(1 Suppl):38-45

Department of Neurosurgery, University of Maryland School of Medicine, Baltimore, Maryland 21201, USA.

Object: Pulmonary complications are the most common acute systemic adverse events following spinal cord injury (SCI), and contribute to morbidity, mortality, and increased length of hospital stay (LOS). Identification of factors associated with pulmonary complications would be of value in prevention and acute care management. Predictors of pulmonary complications after SCI and their effect on neurological recovery were prospectively studied between 2005 and 2009 at the 9 hospitals in the North American Clinical Trials Network (NACTN).

Methods: The authors sought to address 2 specific aims: 1) define and analyze the predictors of moderate and severe pulmonary complications following SCI; and 2) investigate whether pulmonary complications negatively affected the American Spinal Injury Association (ASIA) Impairment Scale conversion rate of patients with SCI. The NACTN registry of the demographic data, neurological findings, imaging studies, and acute hospitalization duration of patients with SCI was used to analyze the incidence and severity of pulmonary complications in 109 patients with early MR imaging and long-term follow-up (mean 9.5 months). Univariate and Bayesian logistic regression analyses were used to analyze the data.

Results: In this study, 86 patients were male, and the mean age was 43 years. The causes of injury were motor vehicle accidents and falls in 80 patients. The SCI segmental level was in the cervical, thoracic, and conus medullaris regions in 87, 14, and 8 patients, respectively. Sixty-four patients were neurologically motor complete at the time of admission. The authors encountered 87 complications in 51 patients: ventilator-dependent respiratory failure (26); pneumonia (25); pleural effusion (17); acute lung injury (6); lobar collapse (4); pneumothorax (4); pulmonary embolism (2); hemothorax (2), and mucus plug (1). Univariate analysis indicated associations between pulmonary complications and younger age, sports injuries, ASIA Impairment Scale grade, ascending neurological level, and lesion length on the MRI studies at admission. Bayesian logistic regression indicated a significant relationship between pulmonary complications and ASIA Impairment Scale Grades A (p = 0.0002) and B (p = 0.04) at admission. Pulmonary complications did not affect long-term conversion of ASIA Impairment Scale grades.

Conclusions: The ASIA Impairment Scale grade was the fundamental clinical entity predicting pulmonary complications. Although pulmonary complications significantly increased LOS, they did not increase mortality rates and did not adversely affect the rate of conversion to a better ASIA Impairment Scale grade in patients with SCI. Maximum canal compromise, maximum spinal cord compression, and Acute Physiology and Chronic Health Evaluation-II score had no relationship to pulmonary complications.
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http://dx.doi.org/10.3171/2012.4.AOSPINE1295DOI Listing
September 2012

A clinical prediction model for long-term functional outcome after traumatic spinal cord injury based on acute clinical and imaging factors.

J Neurotrauma 2012 Sep 31;29(13):2263-71. Epub 2012 Jul 31.

Department of Surgery, Division of Neurosurgery and Spinal Program, University of Toronto, Toronto Western Hospital, Toronto, Ontario, Canada.

To improve clinicians' ability to predict outcome after spinal cord injury (SCI) and to help classify patients within clinical trials, we have created a novel prediction model relating acute clinical and imaging information to functional outcome at 1 year. Data were obtained from two large prospective SCI datasets. Functional independence measure (FIM) motor score at 1 year follow-up was the primary outcome, and functional independence (score ≥ 6 for each FIM motor item) was the secondary outcome. A linear regression model was created with the primary outcome modeled relative to clinical and imaging predictors obtained within 3 days of injury. A logistic model was then created using the dichotomized secondary outcome and the same predictor variables. Model validation was performed using a bootstrap resampling procedure. Of 729 patients, 376 met the inclusion criteria. The mean FIM motor score at 1 year was 62.9 (±28.6). Better functional status was predicted by less severe initial American Spinal Injury Association (ASIA) Impairment Scale grade, and by an ASIA motor score >50 at admission. In contrast, older age and magnetic resonance imaging (MRI) signal characteristics consistent with spinal cord edema or hemorrhage predicted worse functional outcome. The linear model predicting FIM motor score demonstrated an R-square of 0.52 in the original dataset, and 0.52 (95% CI 0.52,0.53) across the 200 bootstraps. Functional independence was achieved by 148 patients (39.4%). For the logistic model, the area under the curve was 0.93 in the original dataset, and 0.92 (95% CI 0.92,0.93) across the bootstraps, indicating excellent predictive discrimination. These models will have important clinical impact to guide decision making and to counsel patients and families.
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http://dx.doi.org/10.1089/neu.2012.2417DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3430477PMC
September 2012

Vertebral body osteolysis following the use of bone morphogenetic protein in spinal surgery: a mimicker of infection.

J Neuroradiol 2012 Dec 24;39(5):354-9. Epub 2012 May 24.

Jackson Memorial Hospital, University of Miami Miller School of Medicine, 1611 NW 12th Avenue, Miami, FL 33136, USA.

This report describes the imaging findings in three patients who developed lumbar spine osteolysis after posterior spinal fusion using rhBMP-2. These cases demonstrate the variable course of osteolysis, as well as the importance of recognizing its radiological appearances to prevent confusion with infection following spinal fusion.
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http://dx.doi.org/10.1016/j.neurad.2012.03.005DOI Listing
December 2012

Effect of primate bone marrow stromal cells on survival and neurite outgrowth.

Neuroreport 2010 Sep;21(13):877-81

Department of Neurological Surgery, Yonsei University College of Medicine, Yonsei University, Seoul, Korea.

We tested whether bone marrow stromal cells (BMSCs) could enhance the survival and neurite growth of dorsal root ganglia (DRG) through substrate effects or secreted factors. Our results showed that in DRG with BMSCs and BMSC-conditioned media cultures compared with DRG-fibroblast cultures, there was a significant increase in the number and length of, area covered by, and number of cells with definite neurites. In cytokine assays with conditioned media, vascular endothelial growth factor, granulocyte macrophage colony-stimulating factor, and IL-6 secreted by BMSCs may contribute to observed neurotrophic effects. These findings indicate that BMSCs of adult Macaca fascicularis increased neuronal survival and promoted neurite outgrowth of DRG by means of secretory factors.
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http://dx.doi.org/10.1097/WNR.0b013e32833da3a6DOI Listing
September 2010