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Shanmukha Srinivas, Arvin R. Wali and Martin H. Pham

OBJECTIVE

Riluzole is a glutamatergic modulator that has recently shown potential for neuroprotection after spinal cord injury (SCI). While the effects of riluzole are extensively documented in animal models of SCI, there remains heterogeneity in findings. Moreover, there is a paucity of data on the pharmacology of riluzole and its effects in humans. For the present study, the authors systematically reviewed the literature to provide a comprehensive understanding of the effects of riluzole in SCI.

METHODS

The PubMed database was queried from 1996 to September 2018 to identify animal studies and clinical trials involving riluzole administration for SCI. Once articles were identified, they were processed for year of publication, study design, subject type, injury model, number of subjects in experimental and control groups, dose, timing/route of administration, and outcomes.

RESULTS

A total of 37 studies were included in this study. Three placebo-controlled clinical trials were included with a total of 73 patients with a mean age of 39.1 years (range 18–70 years). For the clinical trials included within this study, the American Spinal Injury Association Impairment Scale distributions for SCI were 42.6% grade A, 25% grade B, 26.6% grade C, and 6.2% grade D. Key findings from studies in humans included decreased nociception, improved motor function, and attenuated spastic reflexes. Twenty-six animal studies (24 in vivo, 1 in vitro, and 1 including both in vivo and in vitro) were included. A total of 520 animals/in vitro specimens were exposed to riluzole and 515 animals/in vitro specimens underwent other treatment for comparison. The average dose of riluzole for intraperitoneal, in vivo studies was 6.5 mg/kg (range 1–10 mg/kg). Key findings from animal studies included behavioral improvement, histopathological tissue sparing, and modified electrophysiology after SCI. Eight studies examined the pharmacology of riluzole in SCI. Key findings from pharmacological studies included riluzole dose-dependent effects on glutamate uptake and its modified bioavailability after SCI in both animal and clinical models.

CONCLUSIONS

SCI has many negative sequelae requiring neuroprotective intervention. While still relatively new in its applications for SCI, both animal and human studies demonstrate riluzole to be a promising pharmacological intervention to attenuate the devastating effects of this condition.

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Joshua D. Burks, Katie L. Gant, James D. Guest, Aria G. Jamshidi, Efrem M. Cox, Kim D. Anderson, W. Dalton Dietrich, Mary Bartlett Bunge, Barth A. Green, Aisha Khan, Damien D. Pearse, Efrat Saraf-Lavi and Allan D. Levi

OBJECTIVE

In 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.

METHODS

The 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.

RESULTS

Imaging 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).

CONCLUSIONS

While 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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Joseph P. Antonios, Ghassan J. Farah, Daniel R. Cleary, Joel R. Martin, Joseph D. Ciacci and Martin H. Pham

Spinal cord injury (SCI) has been associated with a dismal prognosis—recovery is not expected, and the most standard interventions have been temporizing measures that do little to mitigate the extent of damage. While advances in surgical and medical techniques have certainly improved this outlook, limitations in functional recovery continue to impede clinically significant improvements. These limitations are dependent on evolving immunological mechanisms that shape the cellular environment at the site of SCI. In this review, we examine these mechanisms, identify relevant cellular components, and discuss emerging treatments in stem cell grafts and adjuvant immunosuppressants that target these pathways. As the field advances, we expect that stem cell grafts and these adjuvant treatments will significantly shift therapeutic approaches to acute SCI with the potential for more promising outcomes.

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Sanjay S. Dhall, Shekar N. Kurpad, R. John Hurlbert and Praveen V. Mummaneni

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Coleman P. Riordan, Armide Storey, David J. Cote, Edward R. Smith and R. Michael Scott

OBJECTIVE

There are limited data on the long-term outcomes for children undergoing surgical revascularization for moyamoya disease (MMD) in North America. The authors present a series of pediatric MMD patients who underwent a standard revascularization procedure, pial synangiosis, more than 20 years previously at a single institution by a single surgical team.

METHODS

This study is a retrospective review of all patients aged 21 years or younger treated for MMD at Boston Children’s Hospital who were operated on more than 20 years previously by the senior author (R.M.S.). Radiographic and operative reports, outpatient clinical records, and communications with patients and families were reviewed to document current clinical status, ability to perform daily activities, and concurrent or new medical conditions.

RESULTS

A total of 59 patients (38 female [64.4%], 21 male [35.6%]; median age at surgery 6.2 years [IQR 0.5–21 years]) were identified who were diagnosed with MMD and underwent surgical revascularization procedures more than 20 years previously. Clinically, all but 2 patients (96.6%) presented with the following symptoms alone or in combination: 43 (73%) presented with stroke, 22 (37%) with transient ischemic attack, 12 (20%) with seizures, 7 (12%) with headache, 3 (5%) with choreiform movements, and 2 (3%) with hemorrhage; MMD was incidentally detected in 2 patients (3%). Five patients had unilateral MMD at presentation, but 3 of these ultimately progressed to develop bilateral MMD after an average of 16 months; therefore, pial synangiosis was ultimately performed in a total of 116 hemispheres during the study period. Clinical follow-up was available at a median interval of 20.6 years (IQR 16.1–23.2 years). Modified Rankin Scale scores were stable or improved in 43 of 50 patients with evaluable data; 45 of 55 are currently independent. There were 6 patient deaths (10.2%; 3 due to intracranial hemorrhage, 2 due to tumor-related complications, and 1 due to pulmonary artery stenosis), 4 of whom had a history of previous cranial radiation. One patient (1.7%) experienced a late stroke. Synangiosis vessels remained patent on all available late MRI and MRA studies. Four patients reported uneventful pregnancies and vaginal deliveries years following their revascularization procedures.

CONCLUSIONS

Revascularization for MMD by pial synangiosis appears to confer protection from stroke for pediatric patients over long-term follow-up. A history of cranial radiation was present in 4 of the 6 patients who died and in the lone patient with late stroke. Most patients can expect productive, independent lives following revascularization surgery in the absence of significant preoperative neurological deficits and comorbidities.

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Orel A. Zaninovich, Mauricio J. Avila, Matthew Kay, Jennifer L. Becker, R. John Hurlbert and Nikolay L. Martirosyan

OBJECTIVE

Diffusion tensor imaging (DTI) is an MRI tool that provides an objective, noninvasive, in vivo assessment of spinal cord injury (SCI). DTI is significantly better at visualizing microstructures than standard MRI sequences. In this imaging modality, the direction and amplitude of the diffusion of water molecules inside tissues is measured, and this diffusion can be measured using a variety of parameters. As a result, the potential clinical application of DTI has been studied in several spinal cord pathologies, including SCI. The aim of this study was to describe the current state of the potential clinical utility of DTI in patients with SCI and the challenges to its use as a tool in clinical practice.

METHODS

A search in the PubMed database was conducted for articles relating to the use of DTI in SCI. The citations of relevant articles were also searched for additional articles.

RESULTS

Among the most common DTI metrics are fractional anisotropy, mean diffusivity, axial diffusivity, and radial diffusivity. Changes in these metrics reflect changes in tissue integrity. Several DTI metrics and combinations thereof have demonstrated significant correlations with clinical function both in model species and in humans. Its applications encompass the full spectrum of the clinical assessment of SCI including diagnosis, prognosis, recovery, and efficacy of treatments in both the spinal cord and potentially the brain.

CONCLUSIONS

DTI and its metrics have great potential to become a powerful clinical tool in SCI. However, the current limitations of DTI preclude its use beyond research and into clinical practice. Further studies are needed to significantly improve and resolve these limitations as well as to determine reliable time-specific changes in multiple DTI metrics for this tool to be used accurately and reliably in the clinical setting.

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David J. Wallace, Naomi L. Sayre, T. Tyler Patterson, Susannah E. Nicholson, Donald Hilton and Ramesh Grandhi

In addition to standard management for the treatment of the acute phase of spinal cord injury (SCI), implementation of novel neuroprotective interventions offers the potential for significant reductions in morbidity and long-term health costs. A better understanding of the systemic changes after SCI could provide insight into mechanisms that lead to secondary injury. An emerging area of research involves the complex interplay of the gut microbiome and the CNS, i.e., a brain–gut axis, or perhaps more appropriately, a CNS–gut axis. This review summarizes the relevant literature relating to the gut microbiome and SCI. Experimental models in stroke and traumatic brain injury demonstrate the bidirectional communication of the CNS to the gut with postinjury dysbiosis, gastrointestinal-associated lymphoid tissue–mediated neuroinflammatory responses, and bacterial-metabolite neurotransmission. Similar findings are being elucidated in SCI as well. Experimental interventions in these areas have shown promise in improving functional outcomes in animal models. This commensal relationship between the human body and its microbiome, particularly the gut microbiome, represents an exciting frontier in experimental medicine.

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Michael C. Jin, Zachary A. Medress, Tej D. Azad, Vanessa M. Doulames and Anand Veeravagu

Recent advances in stem cell biology present significant opportunities to advance clinical applications of stem cell–based therapies for spinal cord injury (SCI). In this review, the authors critically analyze the basic science and translational evidence that supports the use of various stem cell sources, including induced pluripotent stem cells, oligodendrocyte precursor cells, and mesenchymal stem cells. They subsequently explore recent advances in stem cell biology and discuss ongoing clinical translation efforts, including combinatorial strategies utilizing scaffolds, biogels, and growth factors to augment stem cell survival, function, and engraftment. Finally, the authors discuss the evolution of stem cell therapies for SCI by providing an overview of completed (n = 18) and ongoing (n = 9) clinical trials.

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Surgery for nerve injury: current and future perspectives

JNSPG 75th Anniversary Invited Review Article

Rajiv Midha and Joey Grochmal

In this review article, the authors offer their perspective on nerve surgery for nerve injury, with a focus on recent evolution of management and the current surgical management. The authors provide a brief historical perspective to lay the foundations of the modern understanding of clinical nerve injury and its evolving management, especially over the last century. The shift from evaluation of the nerve injury using macroscopic techniques of exploration and external neurolysis to microscopic interrogation, interfascicular dissection, and internal neurolysis along with the use of intraoperative electrophysiology were important advances of the past 50 years. By the late 20th century, the advent and popularization of interfascicular nerve grafting techniques heralded a major advance in nerve reconstruction and allowed good outcomes to be achieved in a large percentage of nerve injury repair cases. In the past 2 decades, there has been a paradigm shift in surgical nerve repair, wherein surgeons are not only directing the repair at the injury zone, but also are deliberately performing distal-targeted nerve transfers as a preferred alternative in an attempt to restore function. The peripheral rewiring approach allows the surgeon to convert a very proximal injury with long regeneration distances and (often) uncertain outcomes to a distal injury and repair with a greater potential of regenerative success and functional recovery. Nerve transfers, originally performed as a salvage procedure for severe brachial plexus avulsion injuries, are now routinely done for various less severe brachial plexus injuries and many other proximal nerve injuries, with reliably good to even excellent results. The outcomes from nerve transfers for select clinical nerve injury are emphasized in this review. Extension of the rewiring paradigm with nerve transfers for CNS lesions such as spinal cord injury and stroke are showing great potential and promise. Cortical reeducation is required for success, and an emerging field of rehabilitation and restorative neurosciences is evident, which couples a nerve transfer procedure to robotically controlled limbs and mind-machine interfacing. The future for peripheral nerve repair has never been more exciting.

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Darryl Lau, Cecilia L. Dalle Ore, Phiroz E. Tarapore, Michael Huang, Geoffrey Manley, Vineeta Singh, Praveen V. Mummaneni, Michael Beattie, Jacqueline Bresnahan, Adam R. Ferguson, Jason F. Talbott, William Whetstone and Sanjay S. Dhall

OBJECTIVE

The elderly are a growing subpopulation within traumatic spinal cord injury (SCI) patients. Studies have reported high morbidity and mortality rates in elderly patients who undergo surgery for SCI. In this study, the authors compare the perioperative outcomes of surgically managed elderly SCI patients with those of a younger cohort and those reported in the literature.

METHODS

Data on a consecutive series of adult traumatic SCI patients surgically managed at a single institution in the period from 2007 to 2017 were retrospectively reviewed. The cohort was divided into two groups based on age: younger than 70 years and 70 years or older. Assessed outcomes included complications, in-hospital mortality, intensive care unit (ICU) stay, hospital length of stay (LOS), disposition, and neurological status.

RESULTS

A total of 106 patients were included in the study: 83 young and 23 elderly. The two groups were similar in terms of imaging features (cord hemorrhage and fracture), operative technique, and American Spinal Injury Association Impairment Scale (AIS) grade. The elderly had a significantly higher proportion of cervical SCIs (95.7% vs 71.1%, p = 0.047). There were no significant differences between the young and the elderly in terms of the ICU stay (13.1 vs 13.3 days, respectively, p = 0.948) and hospital LOS (23.3 vs 21.7 days, p = 0.793). Elderly patients experienced significantly higher complication (73.9% vs 43.4%, p = 0.010) and mortality (13.0% vs 1.2%, p = 0.008) rates; in other words, the elderly patients had 1.7 times and 10.8 times the rate of complications and mortality, respectively, than the younger patients. No elderly patients were discharged home (0.0% vs 18.1%, p = 0.029). Discharge AIS grade and AIS grade change were similar between the groups.

CONCLUSIONS

Elderly patients had higher complication and mortality rates than those in younger patients and were less likely to be discharged home. However, it does seem that mortality rates have improved compared to those in prior historical reports.