Improving glioma drug delivery: A multifaceted approach for glioma drug development.

Glioma is one of the most common central nervous system (CNS) cancers that can be found within the brain and the spinal cord. One of the pressing issues plaguing the development of therapeutics for glioma originates from the selective and semipermeable CNS membranes: the blood-brain barrier (BBB) and blood-spinal cord barrier (BSCB). It is difficult to bypass these membranes and target the desired cancerous tissue because the purpose of the BBB and BSCB is to filter toxins and foreign material from invading CNS spaces. There are currently four varieties of Food and Drug Administration (FDA)-approved drug treatment for glioma; yet these therapies have limitations including, but not limited to, relatively low transmission through the BBB/BSCB, despite pharmacokinetic characteristics that allow them to cross the barriers. Steps must be taken to improve the development of novel and repurposed glioma treatments through the consideration of pharmacological profiles and innovative drug delivery techniques. This review addresses current FDA-approved glioma treatments' gaps, shortcomings, and challenges. We then outline how incorporating computational BBB/BSCB models and innovative drug delivery mechanisms will help motivate clinical advancements in glioma drug delivery. Ultimately, considering these attributes will improve the process of novel and repurposed drug development in glioma and the efficacy of glioma treatment.

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.

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.

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.

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.

Recovery of shoulder abduction in traumatic brachial plexus palsy: a systematic review and meta-analysis of nerve transfer versus nerve graft.

Brachial plexus palsy is a surgically manageable condition. Re-animating the shoulder is a high priority for restoring upper extremity function. Methods for reinnervating injured nerves include the transfer of a healthy nerve or fascicle distal to the site of injury, or grafting a healthy sensory nerve to restore motor function. Studies aiming to compare these two techniques for restoring shoulder abduction have yielded conflicting results. We conducted a systematic review and meta-analysis following the PRISMA guidelines. We reviewed the PubMed database for studies comparing nerve transfer and nerve grafting for shoulder abduction published by December 2018. Outcomes using the Medical Research Scale (MRC) for muscle strength were assessed using a random effects model meta-analysis. Five studies comprising a total of 212 patients (n = 158, nerve transfer; n = 54, nerve grafts) were used for the analysis. The rate of functional recovery of shoulder function was slightly better for nerve transfer (n = 114/158, 72%) than for nerve graft patients (n = 36/54, 67%). However, this was not statistically significant (OR 1.34, 95% CI 0.27-6.72, I2 = 62.9%). Nerve transfer and grafting are similarly effective in terms of shoulder abduction. Future prospective studies are needed to validate our results and identify the optimal shoulder re-animation strategy in patients with brachial plexus injuries.

Functional restoration of elbow flexion in nonobstetric brachial plexus injuries: A meta-analysis of nerve transfers versus grafts.

Restoration of elbow flexion is the priority in traumatic brachial plexus injuries. Surgical approaches commonly include nerve transfers and nerve grafting. Our objective was to evaluate the safety and efficacy profile of nerve transfers versus grafting for traumatic nonobstetric brachial plexus injuries. METHODS: This systematic literature review was performed according to the PRISMA guidelines. A random-effects model meta-analysis was conducted, and the I-square was used to assess heterogeneity. The Medical Research Scale (MRC) score was used to assess the efficacy of the procedures. RESULTS: Nine studies comprising 490 patients overall were identified. In the pooled analysis, functional recovery of elbow flexion defined as MRC ≥ M3, was superior in the transfer (N = 272/350, 77.7%) compared to the graft group (N = 99/140, 70.7%); however statistical significance was not reached (OR: 1.95; 95%CI: 0.79-4.83; I2 : 58.8%). However, the odds for successful restoration of elbow flexion (MRC≥M3) were significantly higher when the ulnar (OR:12.20; 95%CI:3.05-48.80; I2 :0%) or pectoral nerves (OR: 9.69; 95% CI: 1.83-51.25; I2 : 0%) were used as healthy donors for the transfer compared to the graft procedures. Results between the two groups were similar when the intercostal, spinal accessory, thoracodorsal, contralateral C7 and phrenic nerves were used as donors for the transfer procedures. CONCLUSIONS: The ulnar or pectoral nerve transfer to musculocutaneous is associated with statistically significant superior rates of elbow flexion recovery as compared to graft. No differences were identified in the pooled analysis or the subgroups of other donors used in nerve transfers. Future randomized studies or prospective cohorts are needed to validate our results.

Neurosurgeons' Armamentarium for the Management of Refractory Postherpetic Neuralgia: A Systematic Literature Review.

BACKGROUND/AIMS: Postherpetic neuralgia (PHN) can be refractory to both medical and minimally invasive treatments. Its complex pathophysiology explains the numerous neurosurgical procedures that have been implemented through the years. Our objective was to summarize all available neurosurgical strategies for the management of resistant PHN and evaluate their respective safety and efficacy outcomes. METHODS: A comprehensive systematic review was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. RESULTS: A total of 38 studies comprising 811 patients with refractory PHN were included. The safety and efficacy of the following procedures were investigated: spinal cord stimulation (SCS), dorsal root entry zone (DREZ) lesioning, intrathecal drug delivery, caudalis DREZ lesioning, dorsal root ganglion (DRG) radiofrequency lesioning, peripheral nerve stimulation, gamma knife surgery, deep brain stimulation, cordotomy, percutaneous radiofrequency rhizotomy and Gasserian ganglion stimulation. CONCLUSIONS: There are several available neurosurgical approaches for recalcitrant PHN including neuromodulatory and ablative procedures. It is suggested that patients with resistant PHN undergo minimally invasive procedures first, including SCS, peripheral nerve stimulation or DRG radiofrequency lesioning. More invasive procedures should be reserved for refractory cases. Comparative studies are needed in order to construct a PHN neurosurgical management algorithm.

Frameless Stereotactic Targeting of the Cerebellar Dentate Nucleus in Nonhuman Primates: Translatable Model for the Surgical Delivery of Gene Therapy.

BACKGROUND: Stereotactic targeting techniques in nonhuman primate (NHP) models are often utilized in the preclinical investigation of new drug therapies with the goal of demonstrating accurate and reliable delivery of a therapy to the target tissue. However, targeting certain neuroanatomical structures can be challenging. The deep cerebellar nuclei, specifically the dentate nucleus, are potential stereotactic targets for the treatment of certain ataxias. Currently, there are no detailed techniques describing frameless targeting of these structures in a NHP model. A well-defined, accurate, and reliable stereotactic surgical approach to the dentate in these animal models is critical to prove the feasibility and safety of drug delivery in order to develop clinical protocols. METHODS: Frameless stereotactic neuronavigation was employed to target the bilateral dentate nuclei of the cerebellum in four healthy juvenile Cynomolgus monkeys via a suboccipital, transcerebellar approach. The precision and accuracy of the targeting were evaluated radiologically and histologically. RESULTS: Using the described surgical methodology, we were successful in hitting the target deep cerebellar nuclei seven out of eight times. CONCLUSION: Frameless stereotactic targeting of the cerebellar dentate nuclei in NHPs for future investigational drug delivery is feasible, safe, and accurate as described by this report. Potential areas for improving the technique are discussed.

Endoscopic third ventriculostomy versus shunt for pediatric hydrocephalus: a systematic literature review and meta-analysis.

BACKGROUND: Optimized management of pediatric hydrocephalus remains the subject of debate. Ventriculoperitoneal shunt is largely considered the standard of care. However, the advancements and introduction of new cerebrospinal fluid (CSF) diversion approaches including the use of endoscopic third ventriculostomy (ETV) offer appealing alternatives that have been reported in numerous observational series. OBJECTIVE: To evaluate the comparative safety and efficacy of shunting and ETV in pediatric hydrocephalus cases. METHODS: This systematic literature review was performed according to the PRISMA guidelines. Eligible studies were identified through a search of PubMed (Medline) and Cochrane until October 2018. A random effects model meta-analysis was conducted and the I-square was used to assess heterogeneity. The ROBINS-1 tool and Cochrane tool were used to assess risk of bias in the observational and randomized studies, respectively. RESULTS: Fourteen studies including 8419 patients were identified. Patients in the ETV group had a statistically significant lower risk of infection compared to shunt (OR: 0.19; 95% CI: 0.07-0.53; I2: 0%). All-cause mortality (OR: 0.77; 95% CI: 0.35-1.68; I2: 0%), post-operative CSF leak (OR: 1.53; 95% CI: 0.37-6.31; I2: 0%), and reoperation rates were similar between the two study groups (OR: 0.72; 95% CI: 0.39-1.32; I2: 93.5%). Subgroup analyses for re-operation demonstrated that ETV in Africa (OR: 0.13; 95% CI: 0.03-0.48; I2: 0%) and Europe (OR: 0.39; 95% CI: 0.30-0.52; I2:1.4%) was associated with significantly lower odds of re-operation compared to shunt, but not in USA/Canada (OR: 1.49; 95% CI: 0.85-2.63; I2:86.2%). Meta-regression analyses of age and duration of follow-up did not affect re-operation rates. CONCLUSIONS: ETV was associated with a statistically significant lower risk of procedure-related infection compared to shunt. All-cause mortality, CSF leak, and re-operation rates were similar between the study groups. Subgroup analysis based on the geographic region showed that ETV is associated with statistically significant lower odds for re-operation in Europe and Africa, but not in USA/Canada. Future RCTs are needed to validate the results of this study and elucidate the cause of this heterogeneity.

Elbow flexion in neonatal brachial plexus palsy: a meta-analysis of graft versus transfer.

BACKGROUND: Functional elbow flexion recovery is one of the main goals of neonatal brachial plexus palsy (NBPP) reconstruction. The current neurosurgical treatment options include nerve grafting and nerve transfer. OBJECTIVE: The present study sought to examine the literature for comparison of functional elbow flexion recovery in NBPP following nerve grafting or nerve transfer. We conducted a systematic literature review and meta-analysis according to PRISMA guidelines. A search was conducted on Pubmed/Medline and Cochrane for eligible studies published until November of 2018. Odd ratios (OR) and 95% confidence intervals (CI) were calculated to compare functional elbow flexion outcomes between nerve graft and nerve transfer. A random effects model meta-analysis was conducted. A Medical Research Council (MRC) score ≥ 3 or Active Movement Scale (AMS) ≥ 5 was considered a functional recovery of elbow flexion. RESULTS: The present study included 194 patients from 1990 to 2015 across five observational trials. Only pediatric patients with obstetric brachial plexus injury were included. The mean patient age at surgery varied between studies from 5.7 months to 11.9 months and mean follow-up from 12 to 70 months. No complications or cases of donor site morbidity were reported. From the included studies, 118 patients were reported with MRC or AMS scoring usable for odd ratio comparison. Functional recovery occurred with nerve transfer in 95.2% of patients (n = 59/62) and with nerve grafting in 96.4% of patients (n = 54/56). Overall, the outcomes for elbow flexion between the groups appeared similar (OR 1.15, 95% CI 0.19-7.08, I2 2.9%). CONCLUSION: Comparing nerve grafting and nerve transfer for NBPP, there is no statistically significant difference in functional elbow flexion recovery.

Coordination of force-generating actin-based modules stabilizes and remodels membranes in vivo.

Membrane remodeling drives a broad spectrum of cellular functions, and it is regulated through mechanical forces exerted on the membrane by cytoplasmic complexes. Here, we investigate how actin filaments dynamically tune their structure to control the active transfer of membranes between cellular compartments with distinct compositions and biophysical properties. Using intravital subcellular microscopy in live rodents we show that a lattice composed of linear filaments stabilizes the granule membrane after fusion with the plasma membrane and a network of branched filaments linked to the membranes by Ezrin, a regulator of membrane tension, initiates and drives to completion the integration step. Our results highlight how the actin cytoskeleton tunes its structure to adapt to dynamic changes in the biophysical properties of membranes.

Spatial and Temporal Coordination of Force-generating Actin-based Modules Drives Membrane Remodeling In Vivo.

Membrane remodeling drives a broad spectrum of cellular functions, and it is regulated through mechanical forces exerted on the membrane by cytoplasmic complexes. Here, we investigate how actin filaments dynamically tune their structure to control the active transfer of membranes between cellular compartments with distinct compositions and biophysical properties. Using intravital subcellular microscopy in live rodents we show that: a lattice composed of linear filaments stabilizes the granule membrane after fusion with the plasma membrane; and a network of branched filaments linked to the membranes by Ezrin, a regulator of membrane tension, initiates and drives to completion the integration step. Our results highlight how the actin cytoskeleton tunes its structure to adapt to dynamic changes in the biophysical properties of membranes.

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.

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.

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.

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.

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.

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.

Transduction of Salivary Gland Acinar Cells with a Novel AAV Vector 44.9.

The loss of salivary gland function caused by radiation therapy of the head and neck or autoimmune disease such as Sjögren's syndrome is a serious condition that affects a patient's quality of life. Due to the combined exocrine and endocrine functions of the salivary gland, gene transfer to the salivary glands holds the potential for developing therapies for disorders of the salivary gland and the expression of therapeutic proteins via the exocrine pathway to the mouth, upper gastrointestinal tract, or endocrine pathway, systemically, into the blood. Recent clinical success with viral vector-mediated gene transfer for the treatment of irradiation-induced damage to the salivary glands has highlighted the need for the development of novel vectors with acinar cell tropism able to result in stable long-term transduction. Previous studies with adeno-associated virus (AAV) focused on the submandibular gland and reported mostly ductal cell transduction. In this study, we have screened AAV vectors for acinar cell tropism in the parotid gland utilizing membrane-tomato floxed membrane-GFP transgenic mice to screen CRE recombinase encoding AAV vectors of different clades to rapidly identify capsid isolates able to transduce salivary gland acinar cells. We determined that AAVRh10 and a novel isolate found as a contaminant of a laboratory stock of simian adenovirus SV15, AAV44.9, are both able to transduce parotid and sublingual acinar cells. Persistence and localization of transduction of these AAVs were tested using vectors encoding firefly luciferase, which was detected 6 months after vector administration. Most luciferase expression was localized to the salivary gland compared to that of distal organs. Transduction resulted in robust secretion of recombinant protein in both blood and saliva. Transduction was species specific, with AAVRh10 having stronger transduction activity in rats compared with AAV44.9 or AAV2 but weaker in human primary salivary gland cells. This work demonstrates efficient transduction of parotid acinar cells by AAV that resulted in secretion of recombinant protein in both serum and saliva.