A Perspective on Electrical Stimulation and Sympathetic Regeneration in Peripheral Nerve Injuries.

Peripheral nerve injuries (PNIs) are common and devastating. The current standard of care relies on the slow and inefficient process of nerve regeneration after surgical intervention. Electrical stimulation (ES) has been shown to both experimentally and clinically result in improved regeneration and functional recovery after PNI for motor and sensory neurons; however, its effects on sympathetic regeneration have never been studied. Sympathetic neurons are responsible for a myriad of homeostatic processes that include, but are not limited to, blood pressure, immune response, sweating, and the structural integrity of the neuromuscular junction. Almost one quarter of the axons in the sciatic nerve are from sympathetic neurons, and their importance in bodily homeostasis and the pathogenesis of neuropathic pain should not be underestimated. Therefore, as ES continues to make its way into patient care, it is not only important to understand its impact on all neuron subtypes, but also to ensure that potential adverse effects are minimized. This piece gives an overview of the effects of ES in animals models and in humans while offering a perspective on the potential effects of ES on sympathetic axon regeneration.

Current and emerging targeted therapies for spinal muscular atrophy.

INTRODUCTION: Spinal muscular atrophy (SMA) is a progressive neurodegenerative disorder caused by insufficiency or total absence of the survival motor neuron protein due to a mutation in the SMN1 gene. The copy number of its paralog, SMN2, influences disease onset and phenotype severity. Current therapeutic approaches include viral and non-viral modalities affecting gene expression. Regulatory-approved drugs Spinraza (Nusinersen), Zolgensma (Onasemnogene abeparvovec), and Evrysdi (Risdiplam) are still being investigated during clinical trials and show benefits in the long-term for symptomatic and pre-symptomatic patients. However, some ongoing interventions require repeated drug administration. AREAS COVERED: In this review, the authors describe the existing therapy based on point of application, focusing on recent clinical trials of antisense oligonucleotides, viral gene therapy, and splice modulators and thepotential routes for correcting the mutation to provide therapeutic levels of SMN protein. EXPERT OPINION: In the opinion of the authors, multiple treatment options for patients with SMA shifted the treatment paradigm from palliative supportive care to improvedmotor function, increased survival, and greater quality of life for such patients. They further believe that the future in SMA treatment development lies incombining existing treatment options, targeting aspects of the disease refractory to these treatments, and using gene editing technologies.

Tumor microenvironment in a minipig model of spinal cord glioma.

BACKGROUND: Spinal cord glioma (SCG) is considered an orphan disease that lacks effective treatment options with margins that are surgically inaccessible and an overall paucity of literature on the topic. The tumor microenvironment is a critical factor to consider in treatment and modeling design, especially with respect to the unresectable tumor edge. Recently, our group developed a high-grade spinal cord glioma (SCG) model in Göttingen minipigs. METHODS: Immunofluorescence and ELISA were performed to explore the microenvironmental features and inflammation cytokines in this minipig SCG model. Protein carbonyl assay and GSH/GSSG assay were analyzed in the core and edge lesions in the minipig SCG model. The primary core and edge cells proliferation rate were shown in vitro, and the xenograft model in vivo. RESULTS: We identified an elevated Ki-67 proliferative index, vascular and pericyte markers, CD31 and desmin in the tumor edge as compared to the tumor core. In addition, we found that the tumor edge demonstrated increased pro-inflammatory and gliomagenic cytokines including TNF-α, IL-1ß, and IL-6. Furthermore, the mediation of oxidative stress is upregulated in the tumor edge. Hypoxic markers had statistically significant increased staining in the tumor core, but were notably still present in the tumor edge. The edge cells cultures derived from SCG biopsy also demonstrated an increased proliferative rate compared to core cell cultures in a xenotransplantation model. CONCLUSIONS: Our study demonstrates heterogeneity in microenvironmental features in our minipig model of high-grade SCG, with a phenotype at the edge showing increased oxidative stress, proliferation, inflammatory cytokines, neovascularization, and decreased but present staining for hypoxic markers. These findings support the utility of this model as a means for investigating therapeutic approaches targeting the more aggressive and surgically unresectable tumor border.

Spinal cord and brain concentrations of riluzole after oral and intrathecal administration: A potential new treatment route for amyotrophic lateral sclerosis.

Riluzole is the only treatment known to improve survival in patients with Amyotrophic Lateral Sclerosis (ALS). However, oral riluzole efficacy is modest at best, further it is known to have large inter-individual variability of serum concentration and clearance, is formulated as an oral drug in a patient population plagued with dysphagia, and has known systemic side-effects like asthenia (limiting patient compliance) and elevated liver enzymes. In this context, we postulated that continuous intrathecal (IT) infusion of low doses of riluzole could provide consistent elevations of the drug spinal cord (SC) concentrations at or above those achieved with oral dosing, without increasing the risk for adverse events associated with systemic drug exposure or off-target side effects in the brain. We developed a formulation of riluzole for IT delivery and conducted our studies in purpose-bred hound dogs. Our non-GLP studies revealed that IT infusion alone was able to increase SC concentrations above those provided by oral administration, without increasing plasma concentrations. We then conducted two GLP studies that combined IT infusion with oral administration at human equivalent dose, to evaluate SC and brain concentrations of riluzole along with assessments of safety and tolerability. In the 6-week study, the highest IT dose (0.2 mg/hr) was well tolerated by the animals and increased SC concentrations above those achieved with oral riluzole alone, without increasing brain concentrations. In the 6-month study, the highest dose tested (0.4 mg/hr) was not tolerated and yielded SC significantly above those achieved in all previous studies. Our data show the feasibility and safety profile of continuous IT riluzole delivery to the spinal cord, without concurrent elevated liver enzymes, and minimal brain concentrations creating another potential therapeutic route of delivery to be used in isolation or in combination with other therapeutics."

Patients with Cognitive Impairment in Parkinson's Disease Benefit from Deep Brain Stimulation: A Case-Control Study.

Background: Deep brain stimulation (DBS) for Parkinson's disease (PD) is generally contraindicated in persons with dementia but it is frequently performed in people with mild cognitive impairment or normal cognition, and current clinical guidelines are primarily based on these cohorts. Objectives: To determine if moderately cognitive impaired individuals including those with mild dementia could meaningfully benefit from DBS in terms of motor and non-motor outcomes. Methods: In this retrospective case-control study, we identified a cohort of 40 patients with PD who exhibited moderate (two or more standard deviations below normative scores) cognitive impairment (CI) during presurgical workup and compared their 1-year clinical outcomes to a cohort of 40 matched patients with normal cognition (NC). The surgery targeted subthalamus, pallidus or motor thalamus, in a unilateral, bilateral or staged approach. Results: At preoperative baseline, the CI cohort had higher Unified Parkinson's Disease Rating Scale (UPDRS) subscores, but similar levodopa responsiveness compared to the NC cohort. The NC and CI cohorts demonstrated comparable degrees of postoperative improvement in the OFF-medication motor scores, motor fluctuations, and medication reduction. There was no difference in adverse event rates between the two cohorts. Outcomes in the CI cohort did not depend on the target, surgical staging, or impaired cognitive domain. Conclusions: Moderately cognitively impaired patients with PD can experience meaningful motor benefit and medication reduction with DBS.

Complication rate of overlapping versus nonoverlapping functional and stereotactic surgery: a retrospective cohort study.

OBJECTIVE: Overlapping surgery, in which one attending surgeon manages two overlapping operating rooms (ORs) and is present for all the critical portions of each procedure, is an important policy that improves healthcare access for patients and case volumes for surgeons and surgical trainees. Despite several studies demonstrating the safety and efficacy of overlapping neurosurgical operations, the practice of overlapping surgery remains controversial. To date, there are no studies that have investigated long-term complication rates of overlapping functional and stereotactic neurosurgical procedures. The primary objective of this study was to investigate the 1-year complication rates and OR times for nonoverlapping versus overlapping functional procedures. The secondary objective was to gain insight into what types of complications are the most prevalent and test for differences between groups. METHODS: Seven hundred eighty-three functional neurosurgical cases were divided into two cohorts, nonoverlapping (n = 342) and overlapping (n = 441). The American Society of Anesthesiologists (ASA) scale score was used to compare the preoperative risk for both cohorts. A complication was defined as any surgically related reason that required readmission, reoperation, or an unplanned emergency department or clinic visit that required intervention. Complications were subdivided into infectious and noninfectious. Chi-square tests, independent-samples t-tests, and uni- and multivariable logistic regressions were used to determine significance. RESULTS: There were no significant differences in mean ASA scale score (2.7 ± 0.6 for both groups, p = 0.997) or overall complication rates (8.8% nonoverlapping vs 9.8% overlapping, p = 0.641) between the two cohorts. Infections accounted for the highest percentage of complications in both cohorts (46.6% vs 41.8%, p = 0.686). There were no statistically significant differences between mean in-room OR time (187.5 ± 141.7 minutes vs 197.1 ± 153.0 minutes, p = 0.373) or mean open-to-close time (112.2 ± 107.9 minutes vs 121.0 ± 123.1 minutes, p = 0.300) between nonoverlapping and overlapping cases. CONCLUSIONS: There was no increased risk of 1-year complications or increased OR time for overlapping functional and stereotactic neurosurgical procedures compared with nonoverlapping procedures.

Surgical Interventions Targeting the Nucleus Caudalis for Craniofacial Pain: A Systematic and Historical Review.

INTRODUCTION: Craniofacial pain is a prevalent group of conditions, and when refractory to conventional treatments, it poses a significant burden. The last decade has seen a renewed interest in the multimodal management of pain. Interventions targeting the nucleus caudalis (NC) of the trigeminocervical complex have been available as a treatment option since the 1930s, yet evidence for efficacy remains limited. MATERIALS AND METHODS: We present a systematic review of the literature providing a historical perspective on interventions targeting the NC leading up to the present. We examine the various intervention techniques, clinical indications, and procedural efficacy. A novel outcome-reporting scheme was devised to enable comparison among studies owing to historically variable reporting methods. RESULTS: A review of the literature revealed 33 retrospective studies published over the last 80 years, reporting on 827 patients. The most common technique was the open NC dorsal root entry zone nucleotomy/tractotomy; however, there has been an emergence of novel approaches such as endoscopic and spinal cord stimulation in the last ten years. Regardless of intervention technique or preoperative diagnosis, 87% of patients showed improvement with treatment. CONCLUSIONS: The literature surrounding NC intervention techniques is reviewed. Recent advancements and the wide range of craniofacial pain syndromes for which these interventions show potential efficacy are discussed. New and less invasive techniques continue to emerge as putative therapeutic options. However, prospective studies are lacking. Furthermore, the evidence supporting even well-established techniques remains of poor quality. Future work should be prospective, use standard outcome reporting, and address efficacy comparisons between intervention type and preoperative diagnosis.

Percutaneous trigeminal tractotomy for trigeminal neuralgia: Postoperative MRI findings.

BACKGROUND AND PURPOSE: Percutaneous trigeminal tractotomy is an ablative procedure that can be used to treat trigeminal neuralgia in patients who have failed prior pharmacologic and surgical treatments. Using perioperative computed tomography (CT) guidance, ablation of the descending spinal trigeminal nucleus and trigeminal tract can be performed precisely to mitigate damage to surrounding structures. These patients are subsequently followed with postoperative imaging and clinical visits to assess long-term pain relief. METHODS: In this report, we present a series of four patients with trigeminal neuralgia who were had refractory disease after prior medical and surgical interventions. These patients underwent CT-guided percutaneous trigeminal tractotomy for pain relief. The patients underwent postoperative MRI and were followed for up to 6 months for long-term clinical outcomes. RESULTS: For intraoperative CT, we find that preprocedure lumbar contrast injection enables better visualization of the cord during placement of the ablation probe. On postoperative imaging, we find that all four patients have hyperintense lesions on T2-weighted MRI that correspond with the location of the trigeminal nucleus and tract. Three patients had short-term pain relief, one of which continued to have long-term relief. CONCLUSION: Intraoperative CT and postoperative MRI serve as useful modalities for confirming localization, evaluating complications, and can be used as a metric for quality control.

Lentiviral-Induced Spinal Cord Gliomas in Rat Model.

Intramedullary spinal cord tumors are a rare and understudied cancer with poor treatment options and prognosis. Our prior study used a combination of PDGF-B, HRAS, and p53 knockdown to induce the development of high-grade glioma in the spinal cords of minipigs. In this study, we evaluate the ability of each vector alone and combinations of vectors to produce high-grade spinal cord gliomas. Eight groups of rats (n = 8/group) underwent thoracolumbar laminectomy and injection of lentiviral vector in the lateral white matter of the spinal cord. Each group received a different combination of lentiviral vectors expressing PDGF-B, a constitutively active HRAS mutant, or shRNA targeting p53, or a control vector. All animals were monitored once per week for clinical deficits for 98 days. Tissues were harvested and analyzed using hematoxylin and eosin (H&E) and immunohistochemical (IHC) staining. Rats injected with PDGF-B+HRAS+sh-p53 (triple cocktail) exhibited statistically significant declines in all behavioral measures (Basso Beattie Bresnahan scoring, Tarlov scoring, weight, and survival rate) over time when compared to the control. Histologically, all groups except the control and those injected with sh-p53 displayed the development of tumors at the injection site, although there were differences in the rate of tumor growth and the histopathological features of the lesions between groups. Examination of immunohistochemistry revealed rats receiving triple cocktail displayed the largest and most significant increase in the Ki67 proliferation index and GFAP positivity than any other group. PDGF-B+HRAS also displayed a significant increase in the Ki67 proliferation index. Rats receiving PDGF-B alone and PDGF-B+ sh-p53 displayed more a significant increase in SOX2-positive staining than in any other group. We found that different vector combinations produced differing high-grade glioma models in rodents. The combination of all three vectors produced a model of high-grade glioma more efficiently and aggressively with respect to behavioral, physiological, and histological characteristics than the rest of the vector combinations. Thus, the present rat model of spinal cord glioma may potentially be used to evaluate therapeutic strategies in the future.

Contralateral C7 Nerve Transfer for Stroke Recovery: New Frontier for Peripheral Nerve Surgery.

Ischemic stroke remains a major cause of disability in the United States and worldwide. Following the large-scale implementation of stroke thrombectomy and the optimization of treatment protocols for acute stroke, the reduction in stroke-associated mortality has resulted in an increased proportion of stroke survivors, many of whom have moderate to severe disability. To date, the treatment of subacute and chronic stroke has remained a challenge. Several approaches, involving pharmacological interventions to promote neuroplasticity, brain stimulation strategies and rehabilitative interventions, are currently being explored at different stages of the translational spectrum, yet level 1 evidence is still limited. In a recent landmark study, surgical intervention using contralateral C7 nerve transfer, an approach used to treat brachial plexus injury, was implemented in patients with chronic stroke, demonstrating an added benefit to standard rehabilitation strategies, leading to improved motor performance and reduced spasticity. The procedure involved the transfer of the C7 nerve root and middle trunk from the uninjured extremity to the injured extremity using a short conduit that allows for faster regeneration and innervation of the injured upper extremity via the ipsilateral (contralesional) hemisphere. In this work, we review the rationale for using contralateral C7 nerve transfer in stroke, describe the surgical intervention with associated variations and limitations, and discuss the current evidence for the efficacy of this technique in ischemic stroke research.

Chemogenetics: Beyond Lesions and Electrodes.

The field of chemogenetics has rapidly expanded over the last decade, and engineered receptors are currently utilized in the lab to better understand molecular interactions in the nervous system. We propose that chemogenetic receptors can be used for far more than investigational purposes. The potential benefit of adding chemogenetic neuromodulation to the current neurosurgical toolkit is substantial. There are several conditions currently treated surgically, electrically, and pharmacologically in clinic, and this review highlights how chemogenetic neuromodulation could improve patient outcomes over current neurosurgical techniques. We aim to emphasize the need to take these techniques from bench to bedside.

A Stereotactic Device for Intraparenchymal Spinal Cord Injections: Latest Developments for Practical Clinical Use.

This manuscript introduces the latest generation of a patient-mounted platform designed for segmental injections of therapeutics direct into the spinal cord parenchyma. It emphasizes its importance and it presents the rationale for developing this delivery methodology. It compares the newest with the previous generations, detailing how the modifications can streamline transportation, assembly, sterilization, and utilization of the platform by different surgeons. Finally, the illustrations depict the main alterations, as well as a cadaveric assessment of the device prototype in the cervical and thoracolumbar regions.

Complication Rates in Early Versus Late Cranioplasty-A 14-Year Single-Center Case Series.

BACKGROUND: Cranioplasty (CP) following decompressive craniectomy (DC) is a common neurosurgical procedure for cranial cosmesis and protection. There is uncertainty regarding the complication rates and potential benefits related to the timing of CP. OBJECTIVE: To investigate the impact of the timing of CP on complication rates for different etiologies of DC. METHODS: A retrospective chart review was performed of all CP cases between 2004 and 2018 for traumatic and nontraumatic indications of DC. Demographics, clinical characteristics, and complications were collected. Early and late CP were defined as replacement of the bone flap at ≤90 and >90 d following DC, respectively. RESULTS: A total of 278 patients were included, receiving 81 early and 197 late CPs. When analyzing all patients, early CP was associated with a statistically significant higher odds of any complication (odds ratio [OR]: 3.25, P < .001), reoperation (OR: 2.57, P = .019), hydrocephalus (OR: 6.03, P = .003), and symptomatic extra-axial collections (OR: 9.22, P = .003). Subgroup analysis demonstrated statistically significant higher odds of these complications only for the CP trauma subgroup, but not the nontrauma subgroup. The odds of complications postCP demonstrated a statistically significant decrease of 4.4% for each week after DC (Unit Odds Ratio [U-OR]: 0.956, P = .0363). CONCLUSION: In our retrospective series, early CP was associated with higher odds of postoperative complications compared to late CP in the trauma subgroup. Greater care should be taken in preoperative planning and increased vigilance postoperatively for complications with this potentially more vulnerable subpopulation. Future prospective controlled trials are needed to elucidate optimal timing for CP.

Programming Parameters and Techniques in Trigeminal Ganglion Stimulation for Intractable Facial Pain.

OBJECTIVES: Atypical facial pain syndromes are challenging disorders to manage and often incur limited benefit with surgery for classical trigeminal neuralgia presentations, such as microvascular decompression or ablative procedures. Neurostimulation of the trigeminal ganglion and peripheral nerves can be effective at treating atypical presentations of trigeminal facial pain affecting the V1-3 dermatomes, and the surgical techniques are well described. The stimulation parameters, however, have thus far received limited description; we therefore sought to describe programming strategies. MATERIALS AND METHODS: We performed a retrospective chart review, examining patients that underwent trigeminal ganglion stimulation (TGS) and nerve branch stimulation for atypical facial pain and trigeminal neuropathic pain, and describe the programming strategies in detail. RESULTS: We describe the use of high-frequency stimulation (1000 Hz), with alteration in pulse width (60-220 msec) and amplitude (0.5-3 V) to achieve effective treatment of refractory trigeminal facial pain. These parameters differ from existing published parameters for trigeminal nerve branch stimulation. We also describe the programming of specific contacts on each lead to target specific aspects of the individual patients' facial pain. CONCLUSIONS: The use of effective programming strategies is critical to the success of neurostimulation surgical treatments; however, the critical details in programming strategies typically receive limited description. We report on the use of several successful programming strategies for TGS, to assist pain providers in successfully applying these surgical techniques in these difficult to manage atypical facial pain syndromes.

Radiofrequency Ablation Through Previously Effective Deep Brain Stimulation Leads for Parkinson Disease: A Retrospective Series.

BACKGROUND: Although deep brain stimulation (DBS) of the subthalamic nucleus (STN) or globus pallidus internus (GPi) is the surgical method of choice to treat the canonical symptoms of Parkinson disease, occasionally surgical sites become infected or the hardware erodes, necessitating explantation. Usual practice is to remove and reimplant replacement leads after tissue healing, leaving patients without the clinical benefits of DBS for several months, and at risk for DBS withdrawal in some, and some patients are no longer good surgical candidates for reimplantation. Radiofrequency ablation through the DBS lead is an option for these patients. METHODS: We performed a retrospective chart review of all patients who underwent radiofrequency ablation of the STN or GPi through indwelling DBS leads performed before hardware removal at our institution. We generated patient-specific anatomic models to determine lesion locations and volumes. RESULTS: Six patients underwent radiofrequency ablation of the STN (n = 4) and GPi (n = 2) through indwelling DBS leads. All 6 of these patients initially showed comparable motor symptom relief to that experienced with DBS before lesioning, with 4 patients sustaining meaningful long-term (≥2 years) improvement. Better outcomes were achieved in those patients with a higher percentage of the planned target lesioned. CONCLUSIONS: Radiofrequency ablation through indwelling DBS leads before explantation could be considered a viable alternative to subsequent reimplantation or stereotactic lesion in patients with Parkinson disease in whom hardware explantation is necessary, if the patient achieved substantive symptom relief with DBS. This approach avoids symptom exacerbation while awaiting revision surgery.

Controlling the Release of Neurotrophin-3 and Chondroitinase ABC Enhances the Efficacy of Nerve Guidance Conduits.

Nerve guidance conduits (NGCs) have the potential to replace autografts in repairing peripheral nerve injuries, but their efficacy still needs to be improved. The efficacy of NGCs is augmented by neurotrophic factors that promote axon growth and by enzymes capable of degrading molecules that inhibit axon growth. In the current study, two types of NGCs loaded with factors (both neurotrophin-3 and chondroitinase ABC) are constructed and their abilities to repair an 8 mm gap in the rat sciatic nerve are examined. The factors are encapsulated in microparticles made of a phase-change material (PCM) or collagen and then sandwiched between two layers of electrospun fibers. The use of PCM allows to achieve pulsed release of the factors upon irradiation with a near-infrared laser. The use of collagen enables slow, continuous release via diffusion. The efficacy is evaluated by measuring compound muscle action potentials (CMAP) in the gastrocnemius muscle and analyzing the nerve histology. Continuous release of the factors from collagen results in enhanced CMAP amplitude and increased axon counts in the distal nerve relative to the plain conduit. In contrast, pulsed release of the same factors from PCM shows a markedly adverse impact on the efficacy, possibly by inhibiting axon growth.

Chimeric Peptide Species Contribute to Divergent Dipeptide Repeat Pathology in c9ALS/FTD and SCA36.

GGGGCC hexanucleotide repeat expansions (HREs) in C9orf72 cause amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) and lead to the production of aggregating dipeptide repeat proteins (DPRs) via repeat associated non-AUG (RAN) translation. Here, we show the similar intronic GGCCTG HREs that causes spinocerebellar ataxia type 36 (SCA36) is also translated into DPRs, including poly(GP) and poly(PR). We demonstrate that poly(GP) is more abundant in SCA36 compared to c9ALS/FTD patient tissue due to canonical AUG-mediated translation from intron-retained GGCCTG repeat RNAs. However, the frequency of the antisense RAN translation product poly(PR) is comparable between c9ALS/FTD and SCA36 patient samples. Interestingly, in SCA36 patient tissue, poly(GP) exists as a soluble species, and no TDP-43 pathology is present. We show that aggregate-prone chimeric DPR (cDPR) species underlie the divergent DPR pathology between c9ALS/FTD and SCA36. These findings reveal key differences in translation, solubility, and protein aggregation of DPRs between c9ALS/FTD and SCA36.

Peripheral trigeminal branch stimulation for refractory facial pain: A single-center experience.

OBJECTIVE: Facial pain refractory to medical treatments may benefit from neurosurgical interventions. Only a few studies have reported on the efficacy of peripheral trigeminal stimulation and more specifically supraorbital nerve (SON) and infraorbital nerve (ION) stimulation for the treatment of facial pain. PATIENTS AND METHODS: In the present study, we identified all patients at our institution who underwent SON and/or ION stimulation for treatment of facial pain due to post-herpetic, traumatic or idiopathic etiology. Relevant pre and post-operative outcomes were analyzed. RESULTS: We identified 15 patients who underwent SON and/or ION stimulation. Among them, 12 (80 %) endorsed >50 % pain relief during the trial stimulation period. After a median follow-up of 5.8 months with permanent implantation, 1 patient (8.3 %) was diagnosed with lead erosion and IPG migration, two patients had lead infections (16.7 %) and one (8.3 %) had wound dehiscence. No lead migrations were identified during the long-term follow-up. The VAS score showed a statistically significant reduction from a median pre-operative score of 7 to a post-operative score of 1.8 (p = 0.011), which corresponded to a 74.3 % average pain reduction. CONCLUSION: SON and/or ION stimulation can be an effective treatment for intractable facial pain due to post-herpetic, traumatic or idiopathic etiology; however the complication rate is relatively high. Future prospective studies with longer follow-up periods are warranted.