Cervical excitatory neurons sustain breathing after spinal cord injury.

Dysfunctional breathing is the main cause of morbidity and mortality after traumatic injury of the cervical spinal cord1,2 and often necessitates assisted ventilation, thus stressing the need to develop strategies to restore breathing. Cervical interneurons that form synapses on phrenic motor neurons, which control the main inspiratory muscle, can modulate phrenic motor output and diaphragmatic function3-5. Here, using a combination of pharmacogenetics and respiratory physiology assays in different models of spinal cord injury, we show that mid-cervical excitatory interneurons are essential for the maintenance of breathing in mice with non-traumatic cervical spinal cord injury, and are also crucial for promoting respiratory recovery after traumatic spinal cord injury. Although these interneurons are not necessary for breathing under normal conditions, their stimulation in non-injured animals enhances inspiratory amplitude. Immediately after spinal cord injury, pharmacogenetic stimulation of cervical excitatory interneurons restores respiratory motor function. Overall, our results demonstrate a strategy to restore breathing after central nervous system trauma by targeting a neuronal subpopulation.

Pathobiology of cervical spondylotic myelopathy.

In this narrative review, we aim to outline what is currently known about the pathophysiology of cervical spondylotic myelopathy (CSM), the most common cause of spinal cord dysfunction. In particular, we note the unique factors that distinguish it from acute spinal cord injury. Despite its common occurrence, the reasons why some patients develop severe symptomatology while others have few or no symptoms despite radiographic evidence confirming similar degrees of compression is poorly understood. Neither is there a clear understanding of why certain patients have a stable clinical myelopathy and others present with only mild myelopathy. Moreover, the precise molecular mechanisms which contribute to the pathogenesis of the disease are incompletely understood. The current treatment method is decompression of the spinal cord but a lack of clinically relevant models of CSM have hindered the understanding of the full pathophysiology which would aid the development of new therapeutic avenues of investigation. Further elucidation of the role of ischemia, currently a source of debate, as well as the complex cascade of biomolecular events as a result of the unique pathophysiology in this disease will pave the way for further neuroprotective strategies to be developed to attenuate the physiological consequences of surgical decompression and augment its benefits.

Riluzole attenuates neuropathic pain and enhances functional recovery in a rodent model of cervical spondylotic myelopathy.

Cervical spondylotic myelopathy (CSM) is the commonest cause of spinal cord impairment worldwide and despite surgical treatment, it is commonly associated with chronic neuropathic pain and neurological impairment. Based on data suggesting a key role of sodium and glutamate mediated cellular injury in models of spinal cord compression, we examined whether riluzole, a sodium channel/glutamate blocker, could improve neurobehavioral outcomes in a rat model of CSM. To produce chronic progressive compression of the cervical spinal cord, we used an established model of graded mechanical cord compromise developed in our laboratory. The chronic (8weeks) mechanical compression of the cervical spinal cord resulted in persistent mechanical allodynia and thermal hyperalgesia at 8weeks. Moreover, we found increased expression of phosphorylated NR1 and NR2B in the dorsal horns as well as astrogliosis and increased microglia expression in the dorsal horns after mechanical compression. Following daily systemic administration for 7weeks after the induction of compression, riluzole (8mg/kg) significantly attenuated forelimb and hindlimb mechanical allodynia and alleviated thermal hyperalgesia in the tail. Importantly, riluzole led to a decrease in swing phase duration, an increase in hind leg swing speed and an increase paw intensity in gait analysis. Riluzole also decreased the number of phosphorylated NR1 and phosphorylated NR2B positive cells in the dorsal horns and the microglia activation in the dorsal horns. Together, our results indicate that systemic riluzole administration during chronic cervical spinal cord compression is effective at protecting spinal cord tissue, preserving neurobehavioral function and alleviating neuropathic pain, possibly by decreasing NMDA receptor phosphorylation in astrocytes and by eliminating microglia activation. As such, riluzole represents a promising clinical treatment for CSM.

Lateral Supraorbital Approach for Microsurgical Clipping of Recurrent Ruptured Fetal Posterior Communicating Artery Aneurysm Initially Treated With Woven Endobridge Embolization and Flow Diversion: 2-Dimensional Operative Video.

Fetal posterior communicating artery (PComA) is a variant of the cerebral vasculature.1 Woven endobridge (WEB) embolization carries a good safety profile as treatment for ruptured wide neck PComA aneurysms, without the need for antiplatelet therapy. However, the reported occlusion rates are not optimal.2 Flow diversion is suboptimal in treating aneurysms originating from fetal PComA.3 Here we present a case of a 78-year-old female patient with a history of ruptured right fetal PComA aneurysm with wide base. It was initially treated with WEB embolization at an outside hospital. After WEB implantation, the initial follow-up of cerebral angiogram (6 months later) demonstrated a neck recurrence measuring 6 × 3 mm. Approximately 1 year after the initial treatment, pipeline embolization was performed and patient was placed on antiplatelet therapy since. Follow-up images demonstrated a 6 mm × 4 mm persistent neck remnant. Her care was transferred to our institution. Cerebral angiogram obtained 36 months post-WEB implantation showed growth of the neck remnant measuring 9 × 8.5 mm. The WEB device was found to be folded in the aneurysmal fundus. Given this was a growing recurrent previously ruptured fetal PComA aneurysm with a pipeline stent in the internal carotid artery the decision was made to retreat with microsurgical clipping; carotid access at the neck was required for proximal control. We achieved complete aneurysm obliteration through a minimal invasive approach. The patient gave informed consent for surgery and video recording. Institutional Review Board approval was deemed unnecessary.

Treatment of Recurrent, Twice Coiled, Previously Ruptured Anterior Inferior Cerebellar Artery-Posterior Inferior Cerebellar Artery Aneurysm With Excision and End-to-End Anastomosis: 2-Dimensional Operative Video.

Anterior inferior cerebellar artery-posterior inferior cerebellar artery (AICA-PICA) variant is a well-established variant of the vertebrobasilar system. AICA-PICA aneurysms are extremely rare.1-3 There are only 12 cases reported in the literature.1-3 Here, we are presenting a case of a previously ruptured AICA-PICA dissecting aneurysm which had undergone coil embolization twice at an outside institution. The aneurysm continued to grow, and therefore, the patient was transferred to our institution for definitive treatment. Placement of a flow diverter was felt not to be feasible because of the acute bend of the vessel at the neck of the aneurysm. After a retrosigmoid craniotomy, the aneurysm sac was opened to untether the coil mass from the neck of the aneurysm. Clip reconstruction was attempted but intraoperative blood flow measurements demonstrated no flow in the distal outflow artery, indicating that the clip was occluding the parent vessel at the neck because of the challenging geometry and atherosclerosis. We then proceeded with an excision and end-to-end anastomosis of the AICA-PICA. The details of vascular reconstruction while the inflow and outflow arteries are at acute angle are described. Intraoperative indocyanine video angiography demonstrated complete exclusion of the aneurysm from the circulation and patency of the bypass. Postoperative computed tomography angiography demonstrated bypass patency. Postoperatively, the patient required a temporary external ventricular drain for hydrocephalus; however, she was eventually discharged home without any neurological deficits. The patient gave informed consent for the surgery and video recording. Institutional Review Board approval was deemed unnecessary.

A novel experimental model of cervical spondylotic myelopathy (CSM) to facilitate translational research.

Cervical spondylotic myelopathy (CSM) is the most common form of spinal cord impairment in adults. However critical gaps in our knowledge of the pathobiology of this disease have limited therapeutic advances. To facilitate progress in the field of regenerative medicine for CSM, we have developed a unique, clinically relevant model of CSM in rats. To model CSM, a piece of synthetic aromatic polyether, to promote local calcification, was implanted microsurgically under the C6 lamina in rats. We included a sham group in which the material was removed 30s after the implantation. MRI confirmed postero-anterior cervical spinal cord compression at the C6 level. Rats modeling CSM demonstrated insidious development of a broad-based, ataxic, spastic gait, forelimb weakness and sensory changes. No neurological deficits were noted in the sham group during the course of the study. Spasticity of the lower extremities was confirmed by a significantly greater H/M ratio in CSM rats in H reflex recordings compared to sham. Rats in the compression group experienced significant gray and white matter loss, astrogliosis, anterior horn cell loss and degeneration of the corticospinal tract. Moreover, chronic progressive posterior compression of the cervical spinal cord resulted in compromise of the spinal cord microvasculature, blood-spinal cord barrier disruption, inflammation and activation of apoptotic signaling pathways in neurons and oligodendrocytes. Finally, CSM rats were successfully subjected to decompressive surgery as confirmed by MRI. In summary, this novel rat CSM model reproduces the chronic and progressive nature of human CSM, produces neurological deficits and neuropathological features accurately mimicking the human condition, is MRI compatible and importantly, allows for surgical decompression.

Occipital Interhemispheric Transtentorial Approach for Microsurgical Resection of a Ruptured Vermian Arteriovenous Malformation: Three-Dimensional Operative Video.

Cerebellar arteriovenous malformations (AVMs) are associated with higher risk of rupture compared with cerebral AVMs.1 Microsurgical resection of a ruptured AVM, measuring 3 cm in its largest dimension, within the cerebellar vermis and right parasagittal cerebellar lobe is demonstrated in Video 1. Cerebral angiography showed major supply from both superior cerebellar arteries and minor supply from a right anterior inferior cerebellar artery-posterior inferior cerebellar artery variant. Venous drainage was through a single ectatic vermian vein draining toward the torcula. Intraoperatively, a second, thrombosed, draining vein connected to the vein of Galen was identified. A right interhemispheric occipital transtentorial approach was elected over the supracerebellar infratentorial approach for early access to the superior cerebellar artery feeding arteries and for an orthogonal rather than a tangential view. The patient was positioned in an ipsilateral lateral position with the head turned 45° toward the floor allowing for gravity retraction of the ipsilateral occipital lobe. An external ventricular drain was also inserted to allow for further relaxation of the occipital lobe. Under neuronavigation guidance, the tentorium was opened allowing immediate visualization of the AVM with early control of the superior cerebellar artery arterial feeders. The AVM was removed using standard microsurgical technique, and hematoma was evacuated. Postoperative cerebral angiography demonstrated no AVM residual. The patient was discharged to a rehabilitation institute with minor residual cerebellar deficits. The patient provided written informed consent for the procedure, video recording, and publication.

Spinal cord injury and degenerative cervical myelopathy.

Spinal cord injury (SCI) often results in impaired respiratory function. Paresis or paralysis of inspiratory and expiratory muscles can lead to respiratory dysfunction depending on the level and severity of the injury, which can affect the management and care of SCI patients. Respiratory dysfunction after SCI is more severe in high cervical injuries, with vital capacity (VC) being an essential indicator of overall respiratory health. Respiratory complications include hypoventilation, a reduction in surfactant production, mucus plugging, atelectasis, and pneumonia. Respiratory management includes mechanical ventilation and tracheostomy in high cervical SCI, while noninvasive ventilation is more common in patients with lower cervical and thoracic injuries. Mechanical ventilation can negatively impact the function of the diaphragm and weaning should start as soon as possible. Patients can sometimes be weaned from mechanical ventilation with assistance of electrical stimulation of the phrenic nerve or the diaphragm. Respiratory muscle training regimens may also improve patients' inspiratory function following SCI. Despite the critical advances in preventing, diagnosing, and treating respiratory complications, they continue to significantly affect persons living with SCI. Additional studies of interventions to reduce respiratory complications are likely to further decrease the morbidity and mortality associated with these injuries.

Minimally Invasive and Outpatient Aneurysm Surgery: New Concepts.

Anterior circulation aneurysms have classically been treated using the pterional (PT) craniotomy. Minimally invasive alternatives to the PT craniotomy have been successfully used to treat vascular pathologies of the anterior circulation. These approaches offer smaller incisions and reduced tissue dissection, resulting in shorter hospital stay, improved cosmetic results, and comparable outcomes for aneurysm treatment compared with classic open approaches. The supraorbital, lateral supraorbital (LSO), mini-PT, minimal interhemispheric, and endoscopic transpterional port approach (ETPA) are each best suited for different aneurysm targets. Outpatient aneurysm surgery has been possible with the use of minimally invasive approaches.

Mir21 modulates inflammation and sensorimotor deficits in cervical myelopathy: data from humans and animal models.

Degenerative cervical myelopathy is a common condition resulting from chronic compression of the spinal cord by degenerating structures of the spine. Degenerative cervical myelopathy present a wide range of outcomes, and the biological factors underlying this variability are poorly understood. Previous studies have found elevated MIR21-5p in the sub-acute and chronic neuroinflammatory environment after spinal cord injury. As chronic spinal cord neuroinflammation is a major feature of degenerative cervical myelopathy, we hypothesized that MIR21-5p may be particularly relevant to disease pathobiology, and could serve as a potential biomarker. A prospective cohort study of 69 human degenerative cervical myelopathy patients (36 male:33 female) between the ages of 30 and 78 years was performed to identify the relationship between MIR21-5p expression, symptom severity and treatment outcomes. Results from this study identified a positive correlation between elevated plasma MIR21-5p expression, initial symptom severity and poor treatment outcomes. Subsequent validation of these relationships using a mouse model of degenerative cervical myelopathy identified a similar elevation of MIR21-5p expression at 6 and 12 weeks after onset, corresponding to moderate to severe neurological deficits. To further determine how MIR21-5p affects cervical myelopathy pathobiology, this mouse model was applied to a Mir21 knockout mouse line. Deletion of the Mir21 gene preserved locomotor function on rotarod and forced swim tests, but also resulted in increased nociception based on tail flick, Von Frey filament and electrophysiological testing. Critically, Mir21 knockout mice also had reduced spinal cord inflammation, demonstrated by the reduction of Iba1+ microglia by ∼50% relative to wild-type controls. In vitro experiments using primary microglial cultures confirmed that MIR21-5p expression was greatly increased after exposure to lipopolysaccharide (pro-inflammatory), Il4 (anti-inflammatory) and hypoxia. Mir21 knockout did not appear to alter the ability of microglia to respond to these stimuli, as expression of key pro- and anti-inflammatory response genes was not significantly altered. However, target prediction algorithms identified the IL6/STAT3 pathway as a potential downstream target of MIR21-5p, and subsequent in vitro testing found that expression of components of the IL6 receptor complex, Il6ra and Il6st, were significantly higher in Mir21 knockout microglia. In aggregate, these data show that Mir21 plays a role in the progression of motor deficits and neuroinflammatory modulation in degenerative cervical myelopathy. Given this role in neuroinflammation, and its association with poor patient outcomes, MIR21-5p represents a potential therapeutic target and a new marker for prognostication.

The Impact of Riluzole on Neurobehavioral Outcomes in Preclinical Models of Traumatic and Nontraumatic Spinal Cord Injury: Results From a Systematic Review of the Literature.

STUDY DESIGN: Systematic review. OBJECTIVE: To evaluate the impact of riluzole on neurobehavioral outcomes in preclinical models of nontraumatic and traumatic spinal cord injury (SCI). METHODS: An extensive search of the literature was conducted in Medline, EMBASE, and Medline in Process. Studies were included if they evaluated the impact of riluzole on neurobehavioral outcomes in preclinical models of nontraumatic and traumatic SCI. Extensive data were extracted from relevant studies, including sample characteristics, injury model, outcomes assessed, timing of evaluation, and main results. The SYRCLE checklist was used to assess various sources of bias. RESULTS: The search yielded a total of 3180 unique citations. A total of 16 studies were deemed relevant and were summarized in this review. Sample sizes ranged from 14 to 90, and injury models included traumatic SCI (n = 9), degenerative cervical myelopathy (n = 2), and spinal cord-ischemia (n = 5). The most commonly assessed outcome measures were BBB (Basso, Beattie, Besnahan) locomotor score and von Frey filament testing. In general, rats treated with riluzole exhibited significantly higher BBB locomotor scores than controls. Furthermore, riluzole significantly increased withdrawal thresholds to innocuous stimuli and tail flick latency following application of radiant heat stimuli. Finally, rats treated with riluzole achieved superior results on many components of gait assessment. CONCLUSION: In preclinical models of traumatic and nontraumatic SCI, riluzole significantly improves locomotor scores, gait function, and neuropathic pain. This review provides the background information necessary to interpret the results of clinical trials on the impact of riluzole in traumatic and nontraumatic SCI.

Sensory cortical control of movement.

Walking in our complex environment requires continual higher order integrated spatiotemporal information. This information is processed in the somatosensory cortex, and it has long been presumed that it influences movement via descending tracts originating from the motor cortex. Here we show that neuronal activity in the primary somatosensory cortex tightly correlates with the onset and speed of locomotion in freely moving mice. Using optogenetics and pharmacogenetics in combination with in vivo and in vitro electrophysiology, we provide evidence for a direct corticospinal pathway from the primary somatosensory cortex that synapses with cervical excitatory neurons and modulates the lumbar locomotor network independently of the motor cortex and other supraspinal locomotor centers. Stimulation of this pathway enhances speed of locomotion, while inhibition decreases locomotor speed and ultimately terminates stepping. Our findings reveal a novel pathway for neural control of movement whereby the somatosensory cortex directly influences motor behavior, possibly in response to environmental cues.

The Natural History of Degenerative Cervical Myelopathy and the Rate of Hospitalization Following Spinal Cord Injury: An Updated Systematic Review.

STUDY METHOD: Systematic review (update). OBJECTIVE: Degenerative cervical myelopathy (DCM) is a degenerative spine disease and the most common cause of spinal cord dysfunction in adults worldwide. The objective of this study is to determine the natural history of DCM by updating the systematic review by Karadimas et al. The specific aims of this review were (1) to describe the natural history of DCM and (2) to determine potential risk factors of disease progression. METHOD: An updated search based on a previous protocol was conducted in PubMed and the Cochrane Collaboration library for studies published between November 2012 and February 15, 2015. RESULTS: The updated search yielded 3 additional citations that met inclusion criteria and reported the incidence of spinal cord injury and severe disability in patients with DCM. Based on 2 retrospective cohort studies, the incidence rate of hospitalization for spinal cord injury is 13.9 per 1000 person-years in patients with cervical spondylotic myelopathy and 4.8 per 1000 person-years in patients with myelopathy secondary to ossification of the posterior longitudinal ligament (OPLL). In a third small prospective study, the risk of being wheelchair bound or bedridden was 66.7% in DCM patients with OPLL. CONCLUSION: The overall level of evidence for these estimated rates of hospitalization following spinal cord injury was rated as low.

Delayed decompression exacerbates ischemia-reperfusion injury in cervical compressive myelopathy.

Degenerative cervical myelopathy (DCM) is the most common progressive nontraumatic spinal cord injury. The most common recommended treatment is surgical decompression, although the optimal timing of intervention is an area of ongoing debate. The primary objective of this study was to assess whether a delay in decompression could influence the extent of ischemia-reperfusion injury and alter the trajectory of outcome in DCM. Using a DCM mouse model, we show that decompression acutely led to a 1.5- to 2-fold increase in levels of inflammatory cytokines within the spinal cord. Delayed decompression was associated with exacerbated reperfusion injury, astrogliosis, and poorer neurological recovery. Additionally, delayed decompression was associated with prolonged elevation of inflammatory cytokines and an exacerbated peripheral monocytic inflammatory response (P < 0.01 and 0.001). In contrast, early decompression led to resolution of reperfusion-mediated inflammation, neurological improvement, and reduced hyperalgesia. Similar findings were observed in subjects from the CSM AOSpine North America and International studies, where delayed decompressive surgery resulted in poorer neurological improvement compared with patients with an earlier intervention. Our data demonstrate that delayed surgical decompression for DCM exacerbates reperfusion injury and is associated with ongoing enhanced levels of cytokine expression, microglia activation, and astrogliosis, and paralleled with poorer neurological recovery.

Degenerative Cervical Myelopathy: Epidemiology, Genetics, and Pathogenesis.

STUDY DESIGN: Review. OBJECTIVE: To formally introduce "degenerative cervical myelopathy" (DCM) as the overarching term to describe the various degenerative conditions of the cervical spine that cause myelopathy. Herein, the epidemiology, pathogenesis, and genetics of conditions falling under this hypernym are carefully described. SUMMARY OF BACKGROUND DATA: Nontraumatic, degenerative forms of cervical myelopathy represent the commonest cause of spinal cord impairment in adults and include cervical spondylotic myelopathy, ossification of the posterior longitudinal ligament, ossification of the ligamentum flavum, and degenerative disc disease. Unfortunately, there is neither a specific term nor a specific diagnostic International Classification of Diseases, Tenth Revision code to describe this collection of clinical entities. This has resulted in the inconsistent use of diagnostic terms when referring to patients with myelopathy due to degenerative disease of the cervical spine. METHODS: Narrative review. RESULTS: The incidence and prevalence of myelopathy due to degeneration of the spine are estimated at a minimum of 41 and 605 per million in North America, respectively. Incidence of cervical spondylotic myelopathy-related hospitalizations has been estimated at 4.04/100,000 person-years, and surgical rates seem to be rising. Pathophysiologically, myelopathy results from static compression, spinal malalignment leading to altered cord tension and vascular supply, and dynamic injury mechanisms. Occupational hazards, including transportation of goods by weight bearing on top of the head, and other risk factors may accelerate DCM development. Potential genetic factors include those related to MMP-2 and collagen IX for degenerative disc disease, and collagen VI and XI for ossification of the posterior longitudinal ligament. In addition, congenital anomalies including spinal stenosis, Down syndrome, and Klippel-Feil syndrome may predispose to the development of DCM. CONCLUSION: Although DCMs can present as separate diagnostic entities, they are highly interrelated, frequently manifest concomitantly, present similarly from a clinical standpoint, and seem to be in part a response to compensate and improve stability due to progressive age and wear of the cervical spine. The use of the term "degenerative cervical myelopathy" is advocated. LEVEL OF EVIDENCE: 5.

Riluzole blocks perioperative ischemia-reperfusion injury and enhances postdecompression outcomes in cervical spondylotic myelopathy.

Although surgical decompression is considered the gold standard treatment for cervical spondylotic myelopathy (CSM), a proportion of cases show postoperative decline or continue to exhibit substantial neurological dysfunction. To investigate this further, we first examined data from the prospective multicenter AOSpine North America CSM study, finding that 9.3% of patients exhibited postoperative functional decline (ΔmJOA, ≤-1) and that 44% of patients were left with substantial neurological impairment 6 months postoperatively. Notably, 4% of patients experienced perioperative neurological complications within 20 days after surgery in otherwise uneventful surgeries. To shed light on the mechanisms underlying this phenomenon and to test a combination therapeutic strategy for CSM, we performed surgical decompression in a rat model of CSM, randomizing some animals to also receive the U.S. Food and Drug Administration-approved drug riluzole. Spinal cord blood flow measurements increased after decompression surgery in rats. CSM rats showed a transient postoperative neurological decline akin to that seen in some CSM patients, suggesting that ischemia-reperfusion injury may occur after decompression surgery. Riluzole treatment attenuated oxidative DNA damage in the spinal cord and postoperative decline after decompression surgery. Mechanistic in vitro studies also demonstrated that riluzole preserved mitochondrial function and reduced oxidative damage in neurons. Rats receiving combined decompression surgery and riluzole treatment displayed long-term improvements in forelimb function associated with preservation of cervical motor neurons and corticospinal tracts compared to rats treated with decompression surgery alone.

Bilateral contusion-compression model of incomplete traumatic cervical spinal cord injury.

Despite the increasing incidence and prevalence of cervical spinal cord injury (cSCI), we lack clinically relevant animal models that can be used to study the pathomechanisms of this injury and test new therapies. Here, we characterize a moderate cervical contusion-compression model in rats that is similar to incomplete traumatic cSCI in humans. We characterized the effects of 18-g clip-compression injury at cervical level C6 over an 8-week recovery period. Using Luxol fast blue/hematoxylin-eosin staining in combination with quantitative stereology, we determined that 18-g injury results in loss of gray matter (GM), white matter (WM), as well as in cavity formation. Magnetization transfer and T2-weighted magnetic resonance imaging were used to analyze lesion dynamics in vivo. This analysis demonstrated that both techniques are able to differentiate between the injury epicenter, subpial rim, and WM distal to the injury. Neurobehavioral assessment of locomotor function using Basso, Beattie, and Bresnahan (BBB) scoring and CatWalk revealed limited recovery from clip-compression injury at C6. Testing of forelimb function using grip strength demonstrated significant forelimb dysfunction, similar to the loss of upper-limb motor function observed in human cSCI. Sensory-evoked potentials recorded from the forelimb and Hoffman reflex recorded from the hindlimb confirmed the fore- and hindlimb deficits observed in our neurobehavioral analysis. Here, we have characterized a clip-compression model of incomplete cSCI that closely models this condition in humans. This work directly addresses the current lack of clinically relevant models of cSCI and will thus contribute to improved success in the translation of putative therapies into the clinic.

Synergistic effects of self-assembling peptide and neural stem/progenitor cells to promote tissue repair and forelimb functional recovery in cervical spinal cord injury.

While neural stem/progenitor cells (NPCs) show promise for traumatic spinal cord injury (SCI), their efficacy in cervical SCI remains to be established. Moreover, their application to SCI is limited by the challenges posed by the lesion including the glial scar and the post-traumatic cavitation. Given this background, we sought to examine the synergistic effect of self-assembling peptide (SAP) molecules, designed to optimize the post-traumatic CNS microenvironment, and NSCs in a clinically-relevant model of contusive/compressive cervical SCI. We injected K2(QL)6K2 (QL6) SAPs into the lesion epicenter 14 days after bilateral clip compression-induced cervical SCI in rats, combined with simultaneous transplantation of neural stem/progenitor cells (NPCs) intraspinally adjacent to the lesion epicenter. The QL6 SAPs reduced the volume of cystic cavitation in the spinal cord lesion. Simultaneously engrafted NPCs preserved motor neurons and attenuated perilesional inflammation. The combination of QL6 and NPCs promoted forelimb neurobehavioral recovery and was associated with significant improvement in forelimb print area and stride length. In summary, we report for the first time histologic and functional benefits in a clinically-relevant model of cervical SCI through the synergistic effects of combined SAP and NPCs.

Delayed administration of a bio-engineered zinc-finger VEGF-A gene therapy is neuroprotective and attenuates allodynia following traumatic spinal cord injury.

Following spinal cord injury (SCI) there are drastic changes that occur in the spinal microvasculature, including ischemia, hemorrhage, endothelial cell death and blood-spinal cord barrier disruption. Vascular endothelial growth factor-A (VEGF-A) is a pleiotropic factor recognized for its pro-angiogenic properties; however, VEGF has recently been shown to provide neuroprotection. We hypothesized that delivery of AdV-ZFP-VEGF--an adenovirally delivered bio-engineered zinc-finger transcription factor that promotes endogenous VEGF-A expression--would result in angiogenesis, neuroprotection and functional recovery following SCI. This novel VEGF gene therapy induces the endogenous production of multiple VEGF-A isoforms; a critical factor for proper vascular development and repair. Briefly, female Wistar rats--under cyclosporin immunosuppression--received a 35 g clip-compression injury and were administered AdV-ZFP-VEGF or AdV-eGFP at 24 hours post-SCI. qRT-PCR and Western Blot analysis of VEGF-A mRNA and protein, showed significant increases in VEGF-A expression in AdV-ZFP-VEGF treated animals (p<0.001 and p<0.05, respectively). Analysis of NF200, TUNEL, and RECA-1 indicated that AdV-ZFP-VEGF increased axonal preservation (p<0.05), reduced cell death (p<0.01), and increased blood vessels (p<0.01), respectively. Moreover, AdV-ZFP-VEGF resulted in a 10% increase in blood vessel proliferation (p<0.001). Catwalk™ analysis showed AdV-ZFP-VEGF treatment dramatically improves hindlimb weight support (p<0.05) and increases hindlimb swing speed (p<0.02) when compared to control animals. Finally, AdV-ZFP-VEGF administration provided a significant reduction in allodynia (p<0.01). Overall, the results of this study indicate that AdV-ZFP-VEGF administration can be delivered in a clinically relevant time-window following SCI (24 hours) and provide significant molecular and functional benefits.

Cervical spondylotic myelopathy: the clinical phenomenon and the current pathobiology of an increasingly prevalent and devastating disorder.

Cervical spondylotic myelopathy (CSM) is a common disorder involving chronic progressive compression of the cervical spinal cord due to degenerative disc disease, spondylosis, or other degenerative pathology. CSM is the most common form of spinal cord impairment and causes functional decline leading to reduced independence and quality of life. Despite a sound understanding of the disease process, clinical presentation and management, a universal definition of CSM and a standardized index of severity are not currently used universally. Work is required to develop a definition and establish clinical predictors of progression to improve management of CSM. Despite advances in decompressive and reconstructive surgery, patients are often left with residual disability. Gaps in knowledge of the pathobiology of CSM have limited therapeutic advances to complement surgery. Although the histopathologic and pathophysiologic similarities between CSM and traumatic spinal cord injury have long been acknowledged, the unique pathomechanisms of CSM remain unexplored. Increased efforts to elucidate CSM pathobiology could lead to the discovery of novel therapeutic targets for human CSM and other spinal cord diseases. Here, the natural history of CSM, epidemiology, clinical presentation, and current methods of clinical management are reported, along with the current state of basic scientific research in the field.