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.

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.

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.

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.

Thoracoscopic delivery of therapeutics in the swine sympathetic chain: Implications for future neuromodulation.

The thoracic sympathetic chain is implicated in several disease processes including palmar hyperhidrosis and complex regional pain syndrome. These diseases are often medically refractory and require surgical treatments including sympathectomies and ganglion blocks. The use of chemogenetic or optogenetic technologies to modulate sympathetic chain activity may be a potential treatment for these diseases. However, there is no established thoracoscopic surgical approach to deliver viral vectors into the thoracic sympathetic chain and ganglia. Our objective was to evaluate the feasibility of thoracoscopic injection of the swine sympathetic chain. Two Landrace farm pigs underwent a novel procedure for thoracoscopic sympathetic chain injections. One was non-survival and one was a five-day survival surgery. Both procedures successfully delivered methylene blue in the thoracic sympathetic chain. Over the five-day postoperative period, the animal displayed stable vital signs. Thoracoscopic targeted injections of the sympathetic chain is a feasible approach to deliver therapeutics in swine. Future studies should investigate the use of transgene expression as a potential means to control sympathetic output for the development of novel therapies for palmar or axillary hyperhidrosis, thoracic neuropathic pain syndromes and select peripheral vascular diseases.

Percutaneous Trigeminal Stimulation for Intractable Facial Pain: A Case Series.

BACKGROUND: Facial pain syndromes can be refractory to medical management and often need neurosurgical interventions. Neuromodulation techniques, including percutaneous trigeminal ganglion (TG) stimulation, are reversible and have emerged as alternative treatment options for intractable facial pain. OBJECTIVE: To report the complication rates and analgesic effects associated with TG stimulation and identify potential predictors for these outcomes. METHODS: A retrospective chart review of 59 patients with refractory facial pain who underwent TG stimulation was conducted. Outcomes following trial period and permanent stimulation were analyzed. Patients with >50% pain relief during trial stimulation received permanent implantation of the stimulation system. RESULTS: Successful trial stimulation was endorsed by 71.2% of patients. During the trial period, 1 TG lead erosion was identified. History of trauma (facial/head trauma and oral surgery) was the only predictor of a failed trial compared to pain of idiopathic etiology (odds ratio: 0.15; 95% CI: 0.03-0.66). Following permanent implantation, approximately 29.6% and 26.5% of patients were diagnosed with lead erosion and infection of the hardware, respectively. TG lead migrations occurred in 11.7% of the patients. The numeric rating scale score showed a statistically significant reduction of 2.49 (95% CI: 1.37-3.61; P = .0001) at an average of 10.8 mo following permanent implantation. CONCLUSION: TG stimulation is a feasible neuromodulatory approach for the treatment of intractable facial pain. Facial/head trauma and oral surgery may predict a nonsuccessful trial stimulation. Future development of specifically designed electrodes for stimulation of the TG, and solutions to reduce lead contamination are needed to mitigate the relatively high complication rate.

Lentiviral Vector Induced Modeling of High-Grade Spinal Cord Glioma in Minipigs.

BACKGROUND: Prior studies have applied driver mutations targeting the RTK/RAS/PI3K and p53 pathways to induce the formation of high-grade gliomas in rodent models. In the present study, we report the production of a high-grade spinal cord glioma model in pigs using lentiviral gene transfer. METHODS: Six Gottingen Minipigs received thoracolumbar (T14-L1) lateral white matter injections of a combination of lentiviral vectors, expressing platelet-derived growth factor beta (PDGF-B), constitutive HRAS, and shRNA-p53 respectively. All animals received injection of control vectors into the contralateral cord. Animals underwent baseline and endpoint magnetic resonance imaging (MRI) and were evaluated daily for clinical deficits. Hematoxylin and eosin (H&E) and immunohistochemical analysis was conducted. Data are presented using descriptive statistics including relative frequencies, mean, standard deviation, and range. RESULTS: 100% of animals (n = 6/6) developed clinical motor deficits ipsilateral to the oncogenic lentiviral injections by a three-week endpoint. MRI scans at endpoint demonstrated contrast enhancing mass lesions at the site of oncogenic lentiviral injection and not at the site of control injections. Immunohistochemistry demonstrated positive staining for GFAP, Olig2, and a high Ki-67 proliferative index. Histopathologic features demonstrate consistent and reproducible growth of a high-grade glioma in all animals. CONCLUSIONS: Lentiviral gene transfer represents a feasible pathway to glioma modeling in higher order species. The present model is the first lentiviral vector induced pig model of high-grade spinal cord glioma and may potentially be used in preclinical therapeutic development programs.

Clinical outcomes of globus pallidus deep brain stimulation for Parkinson disease: a comparison of intraoperative MRI- and MER-guided lead placement.

OBJECTIVE: Deep brain stimulation (DBS) lead placement is increasingly performed with the patient under general anesthesia by surgeons using intraoperative MRI (iMRI) guidance without microelectrode recording (MER) or macrostimulation. The authors assessed the accuracy of lead placement, safety, and motor outcomes in patients with Parkinson disease (PD) undergoing DBS lead placement into the globus pallidus internus (GPi) using iMRI or MER guidance. METHODS: The authors identified all patients with PD who underwent either MER- or iMRI-guided GPi-DBS lead placement at Emory University between July 2007 and August 2016. Lead placement accuracy and adverse events were determined for all patients. Clinical outcomes were assessed using the Unified Parkinson's Disease Rating Scale (UPDRS) part III motor scores for patients completing 12 months of follow-up. The authors also assessed the levodopa-equivalent daily dose (LEDD) and stimulation parameters. RESULTS: Seventy-seven patients were identified (MER, n = 28; iMRI, n = 49), in whom 131 leads were placed. The stereotactic accuracy of the surgical procedure with respect to the planned lead location was 1.94 ± 0.21 mm (mean ± SEM) (95% CI 1.54-2.34) with frame-based MER and 0.84 ± 0.007 mm (95% CI 0.69-0.98) with iMRI. The rate of serious complications was similar, at 6.9% for MER-guided DBS lead placement and 9.4% for iMRI-guided DBS lead placement (RR 0.71 [95% CI 0.13%-3.9%]; p = 0.695). Fifty-seven patients were included in clinical outcome analyses (MER, n = 16; iMRI, n = 41). Both groups had similar characteristics at baseline, although patients undergoing MER-guided DBS had a lower response on their baseline levodopa challenge (44.8% ± 5.4% [95% CI 33.2%-56.4%] vs 61.6% ± 2.1% [95% CI 57.4%-65.8%]; t = 3.558, p = 0.001). Greater improvement was seen following iMRI-guided lead placement (43.2% ± 3.5% [95% CI 36.2%-50.3%]) versus MER-guided lead placement (25.5% ± 6.7% [95% CI 11.1%-39.8%]; F = 5.835, p = 0.019). When UPDRS III motor scores were assessed only in the contralateral hemibody (per-lead analyses), the improvements remained significantly different (37.1% ± 7.2% [95% CI 22.2%-51.9%] and 50.0% ± 3.5% [95% CI 43.1%-56.9%] for MER- and iMRI-guided DBS lead placement, respectively). Both groups exhibited similar reductions in LEDDs (21.2% and 20.9%, respectively; F = 0.221, p = 0.640). The locations of all active contacts and the 2D radial distance from these to consensus coordinates for GPi-DBS lead placement (x, ±20; y, +2; and z, -4) did not differ statistically by type of surgery. CONCLUSIONS: iMRI-guided GPi-DBS lead placement in PD patients was associated with significant improvement in clinical outcomes, comparable to those observed following MER-guided DBS lead placement. Furthermore, iMRI-guided DBS implantation produced a similar safety profile to that of the MER-guided procedure. As such, iMRI guidance is an alternative to MER guidance for patients undergoing GPi-DBS implantation for PD.

Dural Arteriovenous Fistula Presenting as Trigeminal Neuralgia: 2 Case Reports and Review of the Literature.

BACKGROUND: Dural arteriovenous fistulae (dAVFs) can sporadically compress the root entry zone of the trigeminal nerve or the Gasserian ganglion and therefore be a rare cause of isolated or complicated trigeminal neuralgia (TN). CASE DESCRIPTION: We describe 2 cases of TN related to dAVF treated similarly with transarterial embolization but with divergent outcomes. Further, we completed a comprehensive literature review of previously reported cases to date. A sparse but growing literature with regards to this specific and rare but salient cause of TN was noted. The type of dAVF most commonly found to cause TN was that of a tentorial nidus, a lesion generally accepted to be at high risk of hemorrhage and in need of urgent treatment. This warrants imaging for new TN presentations to ensure that a dangerous lesion does not represent the underlying cause, especially when the TN symptoms are comorbid with other symptoms such as a bruit. Treatments pursued span the range of open surgery, endovascular treatment, and radiosurgery with great success in treating both the TN symptoms, as well as the rupture risk of the dAVF itself in most cases. Indeed, endovascular approaches are becoming more widely employed for these cases over time, often resolving the abnormality on first treatment attempt. Other cases reach resolution after employing a combination of treatment modalities. CONCLUSIONS: This work highlights that dAVFs, particularly the tentorial type, are capable of causing TN symptomatically identical to that of other etiologies and that treatment of the dAVF itself is often sufficient.

CRISPR-mediated gene correction links the ATP7A M1311V mutations with amyotrophic lateral sclerosis pathogenesis in one individual.

Amyotrophic lateral sclerosis (ALS) is a severe disease causing motor neuron death, but a complete cure has not been developed and related genes have not been defined in more than 80% of cases. Here we compared whole genome sequencing results from a male ALS patient and his healthy parents to identify relevant variants, and chose one variant in the X-linked ATP7A gene, M1311V, as a strong disease-linked candidate after profound examination. Although this variant is not rare in the Ashkenazi Jewish population according to results in the genome aggregation database (gnomAD), CRISPR-mediated gene correction of this mutation in patient-derived and re-differentiated motor neurons drastically rescued neuronal activities and functions. These results suggest that the ATP7A M1311V mutation has a potential responsibility for ALS in this patient and might be a potential therapeutic target, revealed here by a personalized medicine strategy.

Treatment of neurofibromatosis 1-associated malignant peripheral nerve sheath tumors: a systematic review.

Malignant peripheral nerve sheath tumors (MPNST) are a rare and aggressive group of tumors that are challenging to treat. Neurofibromatosis type 1 (NF-1)-associated MPNSTs have been associated with poorer clinical outcomes. The treatment options for NF-1-associated MPNSTs broadly include surgery (SG), chemotherapy (CT), and adjuvant radiotherapy (RT). Overall, the role and efficacy of CT and RT are unclear. Examination of existing literature for studies reporting on NF-1-associated MPNSTs and respective treatment-related outcomes was conducted. We conducted a systematic review according to PRISMA guidelines in PubMed/Medline and Cochrane databases of studies which reported treatment-specific outcomes in NF-1-associated MPNSTs. The literature search found 444 records after removal of duplicates. The present study included 50 patients across 12 observational studies. All of the included studies reported data on overall survival (OS 52%, n = 26/50) but mean follow-up in months among the studies and among patients varied widely, between 10.85 (SD, ± 10.38) and 192 (SD, ± 98.22). From the included studies, patients underwent either SG alone (n = 21), SG + CT (n = 10), SG + RT (n = 7), or SG + CT + RT (n = 12). The quality of evidence in the literature regarding optimal treatment options for NF-1-associated MPNSTs remains tenuous. Future retrospective and prospective comparative trials should consider adherence to a set of reporting guidelines to improve the quality of evidence in the literature with respect to individual treatment-related outcomes. The need for prospective multi-institutional efforts cannot be overstated.

Minimally Invasive Injection to the Phrenic Nerve in a Porcine Hemidiaphragmatic Paralysis Model: A Pilot Study.

BACKGROUND: Neurodegenerative diseases and spinal cord injury can affect respiratory function often through motor neuron loss innervating the diaphragm. To reinnervate this muscle, new motor neurons could be transplanted into the phrenic nerve (PN), allowing them to extend axons to the diaphragm. These neurons could then be driven by an optogenetics approach to regulate breathing. This type of approach has already been demonstrated in the peripheral nerves of mice. However, there is no established thoracoscopic approach to PN injection. Also, there is currently a lack of preclinical large animal models of diaphragmatic dysfunction in order to evaluate the efficacy of potential treatments. OBJECTIVE: To evaluate the feasibility of thoracoscopic drug delivery into the PN and to assess the viability of hemidiaphragmatic paralysis in a porcine model. METHODS: Two Landrace farm pigs underwent a novel procedure for thoracoscopic PN injections, including 1 nonsurvival and 1 survival surgery. Nonsurvival surgery involved bilateral PN injections and ligation. Survival surgery included a right PN injection and transection proximal to the injection site to induce hemidiaphragmatic paralysis. RESULTS: PN injections were successfully performed in both procedures. The animal that underwent survival surgery recovered postoperatively with an established right hemidiaphragmatic paralysis. Over the 5-d postoperative period, the animal displayed stable vital signs and oxygenation saturation on room air with voluntary breathing. CONCLUSION: Thoracoscopic targeting of the porcine PN is a feasible approach to administer therapeutic agents. A swine model of hemidiaphragmatic paralysis induced by unilateral PN ligation or transection may be potentially used to study diaphragmatic reinnervation following delivery of therapeutics.

Focal and dose-dependent neuroprotection in ALS mice following AAV2-neurturin delivery.

Neurotrophic factors as candidates for ALS therapeutics have previously been studied in the context of attempts to slow disease progression. For a variety of reasons, clinical trials of neurotrophic factors have failed to show efficacy in ALS patients. Previous studies in Parkinson's Disease (PD) models have shown promise with the use of recombinant adeno-associated virus serotype-2 (rAAV2)-neurturin (NRTN) [AAV2-NRTN] providing neuroprotection and behavioral improvements in preclinical models which subsequently resulted in several clinical studies in patients with PD. Given that this neurotrophic compound has not been studied in the context of ALS, we conducted a study of AAV2-NRTN to assess the preclinical safety, tolerability, biodistribution, and efficacy of this compound in an ALS mouse model. SOD1G93A mice were injected with AAV2-NRTN intraspinally at several doses into the cervical spinal cord at 60 days of age. NRTN expression was noted in motor neurons (MNs) of the targeted cervical spinal cord as well as in their neuromuscular junction projections but not in the lumbar spinal cord, which was not targeted. Neuropathologically, a dose-dependent neuroprotective effect was seen in cervical MNs and neuromuscular junctions that was reflected in a slowing of forelimb grip strength decline. As expected, this neuroprotection was found to be focal and was not seen beyond the immediate region of injection. Overall, there were no increases in morbidity, changes in serum chemistries or blood counts and no cases of drug-related mortality. Because there is a broad clinical experience for this compound, these data provide evidence to support further investigation of AAV2-NRTN as a potential ALS therapeutic.

Lot-to-Lot Variation in Adeno-Associated Virus Serotype 9 (AAV9) Preparations.

Viral vectors are complex drugs that pose a particular challenge for manufacturing. Previous studies have shown that, unlike small-molecule drugs, vector preparations do not yield a collection of identical particles. Instead, a mixture of particles that vary in capsid stoichiometry and impurities is created, which may differ from lot to lot. The consequences of this are unclear, but conflicting reports regarding the biological properties of vectors, including transduction patterns, suggest that this variability may have an effect. However, other variables, including differences in animal strains and techniques, make it difficult to identify a cause. Here, we report lot-to-lot variation in spinal cord gray matter transduction following intrathecal delivery of self-complementary adeno-associated virus serotype 9 vectors. Eleven lots of vector were evaluated from six vector cores, including one preclinical/Good Laboratory Practice lot. Eight of the lots, including the preclinical lot, failed to transduce the gray matter, whereas the other three provided robust transduction. The cause for this variation is unknown, but it did not correlate with vector titer, buffer, or purification method. These results highlight the need to identify the cause of this variation and to develop improved production and quality control methods to ensure lot-to-lot consistency of vector potency.

Dorsal Root Ganglion Stimulation for Thoracic Neuralgia: A Report of Six Cases.

OBJECTIVE: Thoracic neuralgia (TN) is a chronic pain syndrome that can be refractory to pharmacologic intervention and management by pain specialists. Dorsal root ganglion (DRG) stimulation has shown promise as a targeted and effective modality compared to traditional therapies for several indications but has not yet been applied in the thoracic region. This study aims to report the outcomes of off-label thoracic DRG stimulation in patients with refractory TN. METHODS: A retrospective chart review was performed at Emory University Hospital for patients who underwent thoracic DRG stimulation in a two-year period. Relevant outcomes for safety and efficacy were evaluated. RESULTS: Six patients were identified that underwent thoracic DRG stimulation for various etiologies of TN, including post-mastectomy, post-herpetic, and post-abdominoplasty neuralgia. All patients initially underwent trial DRG stimulation with a mean pre-operative visual analogue scale (VAS) (0-10) of 6.8 ± 1.6 (range: 4-8). Four of six patients (67%) were non-responders and did not pursue permanent implantation; two experienced pain with stimulation during the trial, and two patients experienced no significant benefit. In addition, all three patients with post-herpetic neuralgia did not respond to treatment. Two of six patients (33%) responded well to stimulation, elected to receive permanent leads, and reported significant pain relief with VAS scores of 0/10 and 1/10, and 100% reduction in morphine equivalent use. Complications included lead migration and need to reset stimulator programming. CONCLUSIONS: DRG stimulation may be an effective therapy for patients experiencing chronic TN as a result of peripheral nerve injury; however, post-herpetic neuralgia may be unresponsive to this treatment. Future prospective studies are warranted to evaluate the feasibility of this procedure in patients with refractory TN.

Case Series: A Minimally Invasive Tunneling Approach for Cubital Tunnel Syndrome.

Background Cubital tunnel syndrome (CuTS) is the second most common peripheral neuropathy in the United States. All three current surgical treatment approaches, consisting of in situ decompression, medial epicondylectomy, and transposition, require large curvilinear incisions and dissections that cross the medial epicondyle. However, the use of a large curvilinear incision may not be necessary for in situ decompression and may be achieved with small incisions proximal and distal to the medial epicondyle. This may limit the risk of peri-incisional pain and numbness, similar to the benefits provided by endoscopy. Objective The aim of this study is to evaluate a minimally invasive tunneling approach for in situ ulnar nerve decompression utilizing 2 cm incisions proximal and distal to the medial epicondyle. Methods A retrospective chart review was performed for patients at Emory University Hospital with CuTS who underwent minimally invasive tunneling for in situ decompression. Seven cases were identified. Patient demographics and data on post-operative complications were collected. Pre-operative severity was graded as a Modified McGowan severity. The primary outcome was evaluated using the post-surgical Messina Criterion. Secondary outcomes were reports of peri-incisional pain or numbness evaluated at follow-up. Descriptive statistics are presented. Results Pre-operatively, one of the seven cases was Grade I McGowan and the remaining six were Grade 2a or 2b. Post-operatively, on the Messina Criterion, four of seven patients were rated as having "Good" outcomes, two of seven had "Fair", while one of seven had "Poor." There was one post-operative surgical site infection. Among the other six cases, there were no reports of peri-incisional pain or numbness. Conclusions The use of less-invasive tunneling approach to in situ decompression yielded positive outcomes in this case series with no reports of peri-incisional pain or numbness. A prospective trial may be useful to explore the theoretical benefits of this novel tunneling approach.