Supinator to posterior interosseous nerve transfer to restore hand opening in brachial plexus and spinal cord injury: a systematic review and individual patient-data meta-analysis.

OBJECTIVE: Cervical spinal cord injury (SCI) and lower trunk brachial plexus injury (BPI) commonly result in hand paralysis. Although restoring hand function is complex and challenging to achieve, regaining volitional hand control drastically enhances functionality for these patients. The authors aimed to systematically review the outcomes of hand-opening function after supinator to posterior interosseous nerve (PIN) transfer. METHODS: A systematic literature review was performed according to the PRISMA guidelines. RESULTS: A total of 16 studies with 88 patients and 119 supinator to PIN transfers were included (87 transfers for SCI and 32 for BPI). In most studies, the time interval from injury to surgery was 6-12 months. Finger extension and thumb extension (Medical Research Council grade ≥ 3/5) recovered in 86.5% (103/119) and 78.1% (93/119) of cases, respectively, over a median follow-up of 19 months. The rates of recovery were similar for the SCI and BPI populations (finger extension, 87.3% in SCI and 84.3% in BPI; thumb extension, 75.8% in SCI and 84.3% in BPI). Type of injury (OR 1.05, 95% CI 0.17-6.4, p = 0.95), time from injury to surgery (OR 1.01, 95% CI 0.8-1.29, p = 0.88), and age (OR 0.97, 95% CI 0.90-1.06, p = 0.60) were not associated with odds of a successful outcome. Duration of follow-up was significantly associated with successful finger extension (OR 1.15, 95% CI 1.01-1.30, p = 0.026). No donor-associated supinator weakness was reported postoperatively given that patients had an intact bicep muscle preoperatively contributing to supination. CONCLUSIONS: Supinator to PIN transfer is a safe and effective procedure that can achieve successful restoration of digital extension in the SCI and BPI population at similar rates. Duration of follow-up was associated with superior outcomes, which was expected.

Neuromuscular consequences of spinal cord injury: New mechanistic insights and clinical considerations.

The spinal cord facilitates communication between the brain and the body, containing intrinsic systems that work with lower motor neurons (LMNs) to manage movement. Spinal cord injuries (SCIs) can lead to partial paralysis and dysfunctions in muscles below the injury. While traditionally this paralysis has been attributed to disruptions in the corticospinal tract, a growing body of work demonstrates LMN damage is a factor. Motor units, comprising the LMN and the muscle fibers with which they connect, are essential for voluntary movement. Our understanding of their changes post-SCI is still emerging, but the health of motor units is vital, especially when considering innovative SCI treatments like nerve transfer surgery. This review seeks to collate current literature on how SCI impact motor units and explore neuromuscular clinical implications and treatment avenues. SCI reduced motor unit number estimates, and surviving motor units had impaired signal transmission at the neuromuscular junction, force-generating capacity, and excitability, which have the potential to recover chronically, yet the underlaying mechanisms are unclear. Furthermore, electrodiagnostic evaluations can aid in assessing the health lower and upper motor neurons, identify suitable targets for nerve transfer surgeries, and detect patients with time sensitive injuries. Lastly, many electrodiagnostic abnormalities occur in both chronic and acute SCI, yet factors contributing to these abnormalities are unknown. Future studies are required to determine how motor units adapt following SCI and the clinical implications of these adaptations.

Segmental infralesional pathological spontaneous activity in subacute traumatic spinal cord injury.

INTRODUCTION/AIMS: There is a dearth of knowledge regarding the status of infralesional lower motor neurons (LMNs) in individuals with traumatic cervical spinal cord injury (SCI), yet there is a growing need to understand how the spinal lesion impacts LMNs caudal to the lesion epicenter, especially in the context of nerve transfer surgery to restore several key upper limb functions. Our objective was to determine the frequency of pathological spontaneous activity (PSA) at, and below, the level of spinal injury, to gain an understanding of LMN health below the spinal lesion. METHODS: Ninety-one limbs in 57 individuals (53 males, mean age = 44.4 ± 16.9 years, mean duration from injury = 3.4 ± 1.4 months, 32 with motor complete injuries), were analyzed. Analysis was stratified by injury level as (1) C4 and above, (2) C5, and (3) C6-7. Needle electromyography was performed on representative muscles innervated by the C5-6, C6-7, C7-8, and C8-T1 nerve roots. PSA was dichotomized as present or absent. Data were pooled for the most caudal infralesional segment (C8-T1). RESULTS: A high frequency of PSA was seen in all infralesional segments. The pooled frequency of PSA for all injury levels at C8-T1 was 68.7% of the limbs tested. There was also evidence of PSA at the rostral border of the neurological level of injury, with 58.3% of C5-6 muscles in those with C5-level injuries. DISCUSSION: These data support a high prevalence of infralesional LMN abnormalities following SCI, which has implications to nerve transfer candidacy, timing of the intervention, and donor nerve options.

Cancer survivors post-chemotherapy exhibit unimpaired short-latency stretch reflexes in the proximal upper extremity.

Oxaliplatin (OX) chemotherapy can lead to long-term sensorimotor impairments in cancer survivors. The impairments are often thought to be caused by OX-induced progressive degeneration of sensory afferents known as length-dependent dying-back sensory neuropathy. However, recent preclinical work has identified functional defects in the encoding of muscle proprioceptors and in motoneuron firing. These functional defects in the proprioceptive sensorimotor circuitry could readily impair muscle stretch reflexes, a fundamental building block of motor coordination. Given that muscle proprioceptors are distributed throughout skeletal muscle, defects in stretch reflexes could be widespread, including in the proximal region where dying-back sensory neuropathy is less prominent. All previous investigations on chemotherapy-related reflex changes focused on distal joints, leading to results that could be influenced by dying-back sensory neuropathy rather than more specific changes to sensorimotor circuitry. Our study extends this earlier work by quantifying stretch reflexes in the shoulder muscles in 16 cancer survivors and 16 healthy controls. Conduction studies of the sensory nerves in hand were completed to detect distal sensory neuropathy. We found no significant differences in the short-latency stretch reflexes (amplitude and latency) of the shoulder muscles between cancer survivors and healthy controls, contrasting with the expected differences based on the preclinical work. Our results may be linked to differences between the human and preclinical testing paradigms including, among many possibilities, differences in the tested limb or species. Determining the source of these differences will be important for developing a complete picture of how OX chemotherapy contributes to long-term sensorimotor impairments.NEW & NOTEWORTHY Our results showed that cancer survivors after oxaliplatin (OX) treatment exhibited stretch reflexes that were comparable with age-matched healthy individuals in the proximal upper limb. The lack of OX effect might be linked to differences between the clinical and preclinical testing paradigms. These findings refine our expectations derived from the preclinical study and guide future assessments of OX effects that may have been insensitive to our measurement techniques.

Postoperative risk of IDH-mutant glioma-associated seizures and their potential management with IDH-mutant inhibitors.

Seizures are a frequent complication of adult-type diffuse gliomas, and are often difficult to control with medications. Gliomas with mutations in isocitrate dehydrogenase 1 or 2 (IDHmut) are more likely than IDH-wild type (IDHwt) gliomas to cause seizures as part of their initial clinical presentation. However, whether IDHmut is also associated with seizures during the remaining disease course, and whether IDHmut inhibitors can reduce seizure risk, are unclear. Clinical multivariable analyses showed that preoperative seizures, glioma location, extent of resection, and glioma molecular subtype (including IDHmut status) all contributed to postoperative seizure risk in adult-type diffuse glioma patients, and that postoperative seizures were often associated with tumor recurrence. Experimentally, the metabolic product of IDHmut, d-2-hydroxyglutarate, rapidly synchronized neuronal spike firing in a seizure-like manner, but only when non-neoplastic glial cells were present. In vitro and in vivo models recapitulated IDHmut glioma-associated seizures, and IDHmut inhibitors currently being evaluated in glioma clinical trials inhibited seizures in those models, independent of their effects on glioma growth. These data show that postoperative seizure risk in adult-type diffuse gliomas varies in large part by molecular subtype, and that IDHmut inhibitors could play a key role in mitigating such risk in IDHmut glioma patients.

Clinical electrodiagnostic evaluation for nerve transfer surgery in spinal cord injury: a new indication and clinical pearls.

In this review, we highlight the important role of the clinical electrodiagnostic (EDX) evaluation after cervical spinal cord injury (SCI). Our discussion focuses on the need for timely, frequent, and accurate EDX evaluations in the context of nerve transfer surgery to restore critical upper limb functions, including elbow extension, hand opening, and hand closing. The EDX evaluation is crucial to define the extent of lower motor neuron lesions and determine candidacy for surgery. We also discuss the important role of the postoperative EDX evaluation in determining prognosis and supporting rehabilitation. We propose a practical framework for EDX evaluation in this clinical setting.

Wirelessly controlled, bioresorbable drug delivery device with active valves that exploit electrochemically triggered crevice corrosion.

Implantable drug release platforms that offer wirelessly programmable control over pharmacokinetics have potential in advanced treatment protocols for hormone imbalances, malignant cancers, diabetic conditions, and others. We present a system with this type of functionality in which the constituent materials undergo complete bioresorption to eliminate device load from the patient after completing the final stage of the release process. Here, bioresorbable polyanhydride reservoirs store drugs in defined reservoirs without leakage until wirelessly triggered valve structures open to allow release. These valves operate through an electrochemical mechanism of geometrically accelerated corrosion induced by passage of electrical current from a wireless, bioresorbable power-harvesting unit. Evaluations in cell cultures demonstrate the efficacy of this technology for the treatment of cancerous tissues by release of the drug doxorubicin. Complete in vivo studies of platforms with multiple, independently controlled release events in live-animal models illustrate capabilities for control of blood glucose levels by timed delivery of insulin.

Botulinum Toxin Conditioning Enhances Motor Axon Regeneration in Mouse and Human Preclinical Models.

BACKGROUND: Peripheral axon regeneration is improved when the nerve lesion under consideration has recently been preceded by another nerve injury. This is known as the conditioning lesion effect (CLE). While the CLE is one of the most robust and well characterized means to enhance motor axon regeneration in experimental models, it is not considered a clinically feasible strategy. A pharmacological means to re-produce the CLE is highly desirable. OBJECTIVE: To test whether chemodenervation with a clinical grade formulation of botulinum toxin A (BoTX) would be sufficient to reproduce the CLE. METHODS: We examined the effects of a 1-week preconditioning administration of BoTX on motor axon regrowth in both a mouse tibial nerve injury and human embryonic stem cell (hESC)-based model. We assessed neuronal reinnervation in vivo (mice) with retrograde tracers and histological analysis of peripheral nerve tissue after injections into the triceps surae muscle group. We assessed motor neuron neurite outgrowth in vitro (hESC) after incubation in BoTX by immunohistochemistry and morphometric analysis. RESULTS: We found that BoTX conditioning treatment significantly enhanced outgrowth of both murine motor axons in vivo and human MN neurites in vitro. CONCLUSIONS: BoTX preconditioning represents a pharmacological candidate approach to enhance motor axon regeneration in specific clinical scenarios such as nerve transfer surgery. Further studies are needed to elucidate the molecular mechanism.

Soft tissue sarcoma affecting the right shoulder of a man with paraplegia from a remote traumatic spinal cord injury: a case report.

INTRODUCTION: People with spinal cord injury (SCI) are getting older due to a combination of increased life expectancy and older age at the time of injury. This trend makes it more likely for these patients to have other chronic health conditions including cancer. Inevitably relatively rare cancers such as soft tissue sarcomas (STS), which are more common with advancing age, will occur in some SCI patients. The present case represents the first report of a limb STS in a patient with chronic paraplegia from a traumatic SCI. CASE PRESENTATION: We report a case of a 50-year-old right handed male with a T6 chronic, complete SCI (American Spinal Injury Association Impairment Scale A) who presented with a large mass involving his right shoulder musculature that was determined to be a high grade spindle cell sarcoma. The patient was followed closely by Physiatry over an approximately 6-month time course including prior to his tumor diagnosis, during the pre-radiation and pre-surgical planning phase, and then post-operatively for his acute inpatient rehabilitation. He was successfully discharged home to live alone in his accessible apartment complex. DISCUSSION: This case is the first ever reported case of a person living with a traumatic SCI who subsequently developed a limb STS. In addition to its novelty, this case illustrates how health conditions such as rare cancers are presenting more often as the chronic SCI population is getting older, which creates both unique diagnostic and management challenges for cancer rehabilitation specialists.

Regulated neuronal neuromodulation via spinal cord expression of the gene for the inwardly rectifying potassium channel 2.1 (Kir2.1).

BACKGROUND: Neuromodulation is used to restore neural function in disorders that stem from an imbalance in the activity of specific neural networks when they prove refractory to pharmacological therapy. The Kir2.1 gene contributes to stabilizing the resting potential below the threshold of activation of voltage-gated sodium channels and action potentials. Therefore, the delivery of the Kir2.1 gene to neuronal cells could reduce the probability of action potential generation, inhibiting excessive neural activity. OBJECTIVE: To address the hypothesis that overexpression of the inwardly rectifying potassium channel 2.1 (Kir2.1) gene could inhibit motor neuron activity and therefore be therapeutically used in gene-based neuromodulation. METHODS: To induce expression of Kir2.1, the inducible RheoSwitch promoter was used and controlled by ligand. In vivo gene expression was accomplished by an adenoviral vector to deliver unilaterally into the lumbar spinal cord of rats. RESULTS: Behavioral assays demonstrated that neuromuscular inhibition was exclusive to rats that received the ligand. Histological analysis also showed evidence of some motor neuron loss in these animals. Behavioral effects of Kir2.1 expression were completely reversible, arguing that the behavioral effect did not result from motor neuron death. CONCLUSION: Delivery of the gene for Kir2.1 inhibits neurons by resisting depolarization to the action potential threshold. Regulated neuronal expression of Kir2.1 may provide an elegant means for neuromodulation in a selected neuronal population.

Brief transvertebral electrical stimulation of the spinal cord improves the specificity of femoral nerve reinnervation.

BACKGROUND: Functional outcomes are generally poor following peripheral nerve injury (PNI). The reason is multifactorial but includes the misdirection of regenerating axons to inappropriate end organs. It has been shown that brief electrical stimulation (Estim) of nerves has the potential to improve the accuracy and rate of peripheral axon regeneration. OBJECTIVE: The present study explores a novel percutaneous transvertebral approach to Estim, which was tested in the mouse femoral nerve model. METHODS: Inspired by the protocol of Gordon and colleagues (ie, 20 Hz, for 1 hour), we applied Estim to the cervicothoracic spinal cord (SC-Estim) to remotely activate lumbar motor neurons following transection and repair of the femoral nerve. Fluorescent dyes were applied to the distal nerve to label reinnervating cells. Sections of nerve were taken to quantify the numbers of reinnervating axons as well as to stain for a known femoral axon guidance molecule-polysialylated neural cell adhesion molecule (PSA-NCAM). RESULTS: In comparison to sham treatment, SC-Estim led to significantly greater expression of PSA-NCAM as well as improved the specificity of motor reinnervation. Interestingly, although SC-Estim did not alter the number of early reinnervating (ie, pioneer) axons, there was a reduction in the number of retrogradely labeled neurons at 2 weeks postrepair. However, by 6 weeks postrepair, there was no difference in the number of neurons that had reinnervated the femoral nerve. CONCLUSIONS: The present findings support the development of SC-Estim as a novel approach to enhance the specificity of reinnervation and potentially improve functional outcomes following PNI.

Intramuscular administration of a VEGF zinc finger transcription factor activator (VEGF-ZFP-TF) improves functional outcomes in SOD1 rats.

Amyotrophic lateral sclerosis (ALS) is characterized by motor neuron loss leading to paralysis and death. Vascular endothelial growth factor (VEGF) has angiogenic, neurotrophic, and neuroprotective properties, and has preserved neuromuscular function and protected motor neurons in rats engineered to overexpress the human gene coding the mutated G93A form of the superoxide dismutase-1 (SOD1). We assessed the effects of intramuscular administration of a plasmid that encodes a zinc finger protein transcription factor (ZFP-TF) engineered to induce VEGF expression in the SOD1 rat model of ALS. Weekly injections of the plasmid preserved ipsilateral hindlimb grip strength and markedly improved rotarod performance in SOD1 rats compared to the vehicle-treated group. The number of motor neurons and the proportion of innervated neuromuscular junctions were similar in both groups. In conclusion, our data suggest that administration of the VEGF-ZFP-TF may be neuroprotective and has potential as a safe and practical approach for the management of motor disability in ALS.

Cervical multilevel intraspinal stem cell therapy: assessment of surgical risks in Gottingen minipigs.

STUDY DESIGN: Assessment of long-term surgical risks from multiple intraspinal cell injections. OBJECTIVE: To prove that multilevel-targeted cell injection to the spinal cord can be a feasible and safe procedure. SUMMARY OF BACKGROUND DATA: Neural cell transplantation has been proposed as a treatment for a variety of neurologic disorders, including degenerative, ischemic, autoimmune, and traumatic etiologies. Among these diseases, the lack of effective treatment for amyotrophic lateral sclerosis has prompted the search for cell-based neuroprotection or motor neuron-replacement therapies. METHODS: Fifteen female minipigs, divided into 3 experimental groups, underwent either 5 or 10 unilateral injections of neural stem cells or 10 vehicle injections into the C3-C5 segments of the spinal cord, using a device and technique developed for safe and accurate injection into the human spinal cord. All animals received intravenous Tacrolimus (0.025 mg/kg) BID during the course of the study. Sensory and motor functions as well as general morbidity were assessed for 28 days. Full necropsy was performed and spinal cords were analyzed for graft survival. This study was performed under Good Laboratory Practice conditions. RESULTS: Neither mortality nor permanent surgical complications were observed within the 28-day study period. All animals returned to preoperative baseline showing full motor function recovery. Graft survival was demonstrated by immunohistochemistry. CONCLUSION: Clinically acceptable neural progenitor survival, distribution, and density were achieved using the number of injections and surgical techniques specifically developed for this purpose.

Cervical spinal cord therapeutics delivery: preclinical safety validation of a stabilized microinjection platform.

OBJECTIVE: The current series represents a preclinical safety validation study for direct parenchymal microinjection of cellular grafts into the ventral horn of the porcine cervical spinal cord. METHODS: Twenty-four 30- to 40-kg female Yorkshire farm pigs immunosuppressed with cyclosporine underwent a cervical laminectomy and ventral horn human neural progenitor cell injection. Cell transplantation in groups 1 to 3 (n = 6 pigs each) was undertaken with the intent of assessing the safety of varied injection volumes: 10, 25, and 50 microL injected at 1, 2.5, and 5 microL/min, respectively. Groups 4 and 5 (n = 3 pigs each) received prolonged immunosuppressant pretreatment in an attempt to demonstrate graft viability. The latter was undertaken in an alternate species (mini-pig versus Yorkshire pig). RESULTS: Neurological morbidity was observed in 1 animal and was attributable to the presence of a resolving epidural hematoma noted at necropsy. Although instances of ventral horn targeting were achieved in all injection groups with a coordinate-based approach, opportunities exist for improvement in accuracy and precision. A relationship between injection volume and graft site cross-sectional area suggested limited reflux. Only animals from group 5 achieved graft survival at a survival end point (t = 1 week). CONCLUSION: This series demonstrated the functional safety of targeted ventral horn microinjection despite evidence for graft site immune rejection. Improvements in graft delivery may be augmented with an adapter to improve control of the cannula entry angle, intraoperative imaging, or larger graft volumes. Finally, demonstration of long-term graft viability in future preclinical toxicity studies may require tailored immunosuppressive therapies, an allograft construct, or tailored choice of host species.

Intraspinal cord delivery of IGF-I mediated by adeno-associated virus 2 is neuroprotective in a rat model of familial ALS.

BACKGROUND: Amyotrophic lateral sclerosis (ALS) is a devastating disease that is characterized by the progressive loss of motor neurons. Patients with ALS usually die from respiratory failure due to respiratory muscle paralysis. Consequently, therapies aimed at preserving segmental function of the respiratory motor neurons could extend life for these patients. Insulin-like growth factor-I (IGF-I) is known to be a potent survival factor for motor neurons. In this study we induced high levels of IGF-I expression in the cervical spinal cord of hSOD1(G93A) rats with intraspinal cord (ISC) injections of an adeno-associated virus serotype 2 vector (CERE-130). This approach reduced the extent of motor neuron loss in the treated segments of the spinal cord. However, a corresponding preservation of motor function was observed in male, but not female, hSOD1(G93A) rats. We conclude that ISC injection of CERE-130 has the potential to protect motor neurons and preserve neuromuscular function in ALS.

Intrinsic neuronal properties control selective targeting of regenerating motoneurons.

Despite advances in microsurgical techniques, recovery of motor function after peripheral nerve injury is often poor because many regenerating axons reinnervate inappropriate targets. Consequently, surgical repair must include treatment strategies that improve motor axon targeting. Development of such treatments will require a better understanding of the molecular mechanisms governing selective motor axon targeting. This study used a well-established model of nerve transection and repair to examine (1) whether intrinsic differences exist between different pools of motoneurons after peripheral nerve injury, (2) if such differences regulate selective axon targeting, (3) if regenerating motor axons must express polysialic acid (PSA) in order to preferentially reinnervate muscle and (4) whether brief electrical stimulation improves regeneration accuracy because it increases PSA expression on regenerating axons. We found that different motor pools differentially express PSA after injury and that the capacity to re-express PSA appears to be an intrinsic neuronal property established during development. Second, motoneuron pools not up-regulating PSA did not preferentially reinnervate muscle after injury. Third, brief electrical stimulation of the proximal nerve stump immediately after injury only improved selective motor axon targeting if the motoneurons were capable of up-regulating PSA. Finally, the benefits of stimulation were completely abolished if PSA was removed from the regenerating axons. These results indicate that (1) intrinsic neuronal differences between motor pools must be considered in the development of treatments designed to improve axon targeting and (2) therapeutics aimed at increasing PSA levels on regenerating motor axons may lead to superior functional outcomes.

Polysialylated neural cell adhesion molecule is necessary for selective targeting of regenerating motor neurons.

It is well established that peripheral nerves regenerate after injury. Therefore, incomplete functional recovery usually results from misguided axons rather than a lack of regeneration per se. Despite this knowledge very little is known about the molecular mechanisms regulating axon guidance during regeneration. In the developing neuromuscular system the neural cell adhesion molecule (NCAM) and its polysialic acid (PSA) moiety are essential for proper motor axon guidance. In this study we used a well established model of nerve transection and repair to examine whether NCAM and/or PSA promotes selective regeneration of femoral motor nerves in wild-type and NCAM (-/-) mice. We found that regenerating axons innervating the muscle pathway and, to a lesser extent, cutaneous axons in the sensory pathway reexpress high levels of PSA during the time when the cut axons are crossing the lesion site. Second, we found that motor neurons in wild-type mice preferentially reinnervated muscle pathways, whereas motor neurons in NCAM (-/-) mice reinnervated muscle and cutaneous pathways with equal preference. Preferential regeneration was not observed in wild-type mice when PSA was removed enzymatically from the regenerating nerve, indicating that this form of selective motor axon targeting requires PSA. Finally, transgenic mice were used to show that the number of collateral sprouts, their field of arborization, and the withdrawal of misprojected axons were all attenuated significantly in mice lacking PSA. These results indicate that regenerating motor axons must express polysialylated NCAM, which reduces axon-axon adhesion and enables motor neurons to reinnervate their appropriate muscle targets selectively.