Core outcomes in nerve surgery: development of a core outcome set for brachial plexus and upper extremity nerve injuries.

OBJECTIVE: When considering traumatic brachial plexus and upper extremity nerve injuries, iatrogenic nerve injuries, and nontraumatic nerve injuries, brachial plexus and upper extremity nerve injuries are commonly encountered in clinical practice. Despite this, data synthesis and comparison of available studies are difficult. This is at least in part due to the lack of standardization in reporting and a lack of a core outcome set (COS). Thus, there is a need for a COS for adult brachial plexus and upper extremity nerve injuries (COS-BPUE). The objective of this study was to develop a COS-BPUE using a modified Delphi approach. METHODS: A 5-stage approach was used to develop the COS-BPUE: 1) consortium development, 2) literature review to identify potential outcome measures, 3) Delphi survey to develop consensus on outcomes for inclusion, 4) Delphi survey to develop definitions, and 5) consensus meeting to finalize the COS and definitions. The study followed the Core Outcome Set-STAndards for Development (COS-STAD) recommendations. RESULTS: The Core Outcomes in Nerve Surgery (COINS) Consortium comprised 23 participants, all neurological surgeons, representing 13 countries. The final COS-BPUE consisted of 36 data points/outcomes covering demographic, diagnostic, patient-reported outcome, motor/sensory outcome, and complication domains. Appropriate instruments, methods of testing, and definitions were set. The consensus minimum duration of follow-up was 24 months, with the consensus optimal time points for assessment being preoperatively and 3, 6, 12, and 24 months postoperatively. CONCLUSIONS: The COINS Consortium developed a consensus COS and provided definitions, methods of implementation, and time points for assessment. The COS-BPUE should serve as a minimum set of data that should be collected in all future neurosurgical studies on adult brachial plexus and upper extremity nerve injuries. Incorporation of this COS should help improve consistency in reporting, data synthesis, and comparability, and should minimize outcome reporting bias.

Functional interactions between neurofibromatosis tumor suppressors underlie Schwann cell tumor de-differentiation and treatment resistance.

Schwann cell tumors are the most common cancers of the peripheral nervous system and can arise in patients with neurofibromatosis type-1 (NF-1) or neurofibromatosis type-2 (NF-2). Functional interactions between NF1 and NF2 and broader mechanisms underlying malignant transformation of the Schwann lineage are unclear. Here we integrate bulk and single-cell genomics, biochemistry, and pharmacology across human samples, cell lines, and mouse allografts to identify cellular de-differentiation mechanisms driving malignant transformation and treatment resistance. We find DNA methylation groups of Schwann cell tumors can be distinguished by differentiation programs that correlate with response to the MEK inhibitor selumetinib. Functional genomic screening in NF1-mutant tumor cells reveals NF2 loss and PAK activation underlie selumetinib resistance, and we find that concurrent MEK and PAK inhibition is effective in vivo. These data support a de-differentiation paradigm underlying malignant transformation and treatment resistance of Schwann cell tumors and elucidate a functional link between NF1 and NF2.

Core outcomes in nerve surgery: development of a core outcome set for ulnar neuropathy at the elbow.

OBJECTIVE: Ulnar neuropathy at the elbow (UNE) is common, affecting 1%-6% of the population. Despite this, there remains a lack of consensus regarding optimal treatment. This is primarily due to the difficulty one encounters when trying to assess the literature. Outcomes are inconsistently reported, which makes comparing studies or developing meta-analyses difficult or even impossible. Thus, there is a need for a core outcome set (COS) for UNE (COS-UNE) to help address this problem. The objective of this study was to utilize a modified Delphi method to develop COS-UNE. METHODS: A 5-stage approach was utilized to develop COS-UNE: stage 1, consortium development; 2, literature review to identify potential outcome measures; 3, Delphi survey to develop consensus on outcomes for inclusion; 4, Delphi survey to develop definitions; and 5, consensus meeting to finalize the COS and definitions. The study followed the Core Outcome Set-STAndards for Development (COS-STAD) recommendations. RESULTS: The Core Outcomes in Nerve Surgery (COINS) Consortium comprised 21 participants, all neurological surgeons representing 11 countries. The final COS-UNE consisted of 22 data points/outcomes covering the domains of demographic characteristics, diagnostics, patient-reported outcomes, motor/sensory outcomes, and complications. Appropriate instruments, methods of testing, and definitions were set. The consensus minimum duration of follow-up was 6 months, with the consensus optimal timepoints for assessment identified as preoperatively and 3, 6, and 12 months postoperatively. CONCLUSIONS: The authors identified consensus data points/outcomes and also provided definitions and specific scales to be utilized to help ensure that clinicians are consistent in their reporting across studies on UNE. This COS should serve as a minimum set of data to be collected in all future neurosurgical studies on UNE. The authors hope that clinicians evaluating ulnar neuropathy will incorporate this COS into routine practice and that future studies will consider this COS in the design phase.

Novel SOX10 indel mutations drive schwannomas through impaired transactivation of myelination gene programs.

BACKGROUND: Schwannomas are common peripheral nerve sheath tumors that can cause severe morbidity given their stereotypic intracranial and paraspinal locations. Similar to many solid tumors, schwannomas and other nerve sheath tumors are primarily thought to arise due to aberrant hyperactivation of the RAS growth factor signaling pathway. Here, we sought to further define the molecular pathogenesis of schwannomas. METHODS: We performed comprehensive genomic profiling on a cohort of 96 human schwannomas, as well as DNA methylation profiling on a subset. Functional studies including RNA sequencing, chromatin immunoprecipitation-DNA sequencing, electrophoretic mobility shift assay, and luciferase reporter assays were performed in a fetal glial cell model following transduction with wildtype and tumor-derived mutant isoforms of SOX10. RESULTS: We identified that nearly one-third of sporadic schwannomas lack alterations in known nerve sheath tumor genes and instead harbor novel recurrent in-frame insertion/deletion mutations in SOX10, which encodes a transcription factor responsible for controlling Schwann cell differentiation and myelination. SOX10 indel mutations were highly enriched in schwannomas arising from nonvestibular cranial nerves (eg facial, trigeminal, vagus) and were absent from vestibular nerve schwannomas driven by NF2 mutation. Functional studies revealed these SOX10 indel mutations have retained DNA binding capacity but impaired transactivation of glial differentiation and myelination gene programs. CONCLUSIONS: We thus speculate that SOX10 indel mutations drive a unique subtype of schwannomas by impeding proper differentiation of immature Schwann cells.

Resident peripheral nerve surgery competence: An assessment of procedural exposure, self-reported competence and technical ability.

BACKGROUND: Identifying peripheral nerve surgery procedure (PNSP) competencies is crucial to ensure adequate resident training. We examine PNSP training at neurosurgical centers in the US and Canada to compare resident-reported competence, PNSP exposure, and resident technical abilities in performing 3 peripheral nerve coaptations (PNC). METHODS: Resident-reported PNSP competence and PNSP exposure data were collected using questionnaires from neurosurgical residents at North American neurosurgical training centers. Exposure and self-reported competency were correlated with technical skills. Technical PNC variables collected included: time-to-completion, nerve-handling from video-analysis, independent and blinded visual-analog-scale (VAS) PNC quality grading by 3 judges, and training level. RESULTS: A total of 40 neurosurgical residents participated in the study. Although self-reported competency scores correlated with procedural exposure (P < 0.01, rs = 0.88), a discrepancy was found between the degree of self-reported competency and amount of exposure. The discrepancy was greater in senior residents. A significant VAS difference was found between PNC types with the direct-suture and connector-assister groups scoring higher than connector-only (P = 0.02, P < 0.01, respectively). No difference was observed between training level and VAS grading, nor time-to completion (P = 0.33 and 0.25, respectively). No correlation was found between self-reported competency performing PNSPs and PNC VAS scores, nor nerve handling. CONCLUSIONS: Despite more exposure and a higher self-reported PNSP competency in senior residents, no difference was seen between senior/junior residents in PNC quality. A discrepancy in PNSP exposure and self-reported competency exists. This information will provide guidance for the direction of resident PNS training.

Appendiceal neurofibroma in a patient with neurofibromatosis 1 and recurrent abdominal infections from ventriculoperitoneal shunt: a case report.

Appendiceal neurofibromas are exceedingly rare, with neither experimental nor observational data to support evidence-based diagnosis or treatment. We describe the case of a 52-year-old woman with neurofibromatosis 1 (NF1) complicated by aqueductal stenosis and resultant hydrocephalus needing a ventriculoperitoneal shunt (VPS). She presented to the emergency department with abdominal pain and was found to have abnormalities in the right hemiabdomen on cross-section imaging, also a Staphylococcus epidermidis growth at the distal portion of the VPS. She was initially treated with two rounds of intravenous antibiotics and VPS removal without improvement. She ultimately underwent an appendectomy, which revealed pathologic evidence of NF. The appendectomy was key to ruling out malignancy, addressing further symptoms and preventing future malignant transformation. This case highlights the importance of including appendiceal neurofibromas in the differential diagnoses of abdominal pain in patients with NF1.

Diagnostic Accuracy of MRI for the Detection of Malignant Peripheral Nerve Sheath Tumors: A Systematic Review and Meta-Analysis.

OBJECTIVE. This systematic review and meta-analysis evaluates the diagnostic accuracy of MRI for differentiating malignant (MPNSTs) from benign peripheral nerve sheath tumors (BPNSTs). MATERIALS AND METHODS. A systematic review of MEDLINE, Embase, Scopus, the Cochrane Library, and the gray literature from inception to December 2019 was performed. Original articles that involved at least 10 patients and that evaluated the accuracy of MRI for detecting MPNSTs were included. Two reviewers independently extracted clinical and radiologic data from included articles to calculate sensitivity, specificity, PPV, NPV, and accuracy. A meta-analysis was performed using a bivariate mixed-effects regression model. Risk of bias was evaluated using QUADAS-2. RESULTS. Fifteen studies involving 798 lesions (252 MPNSTs and 546 BPNSTs) were included in the analysis. Pooled and weighted sensitivity, specificity, and AUC values for MRI in detecting MPNSTs were 68% (95% CI, 52-80%), 93% (95% CI, 85-97%), and 0.89 (95% CI, 0.86-0.92) when using feature combination and 88% (95% CI, 74-95%), 94% (95% CI, 89-96%), and 0.97 (95% CI, 0.95-0.98) using diffusion restriction with or without feature combination. Subgroup analysis, such as patients with neurofibromatosis type 1 (NF1) versus those without NF1, could not be performed because of insufficient data. Risk of bias was predominantly high or unclear for patient selection, mixed for index test, low for reference standard, and unclear for flow and timing. CONCLUSION. Combining features such as diffusion restriction optimizes the diagnostic accuracy of MRI for detecting MPNSTs. However, limitations in the literature, including variability and risk of bias, necessitate additional methodologically rigorous studies to allow subgroup analysis and further evaluate the combination of clinical and MRI features for MPNST diagnosis.

A Safe Transitions Pathway for post-craniotomy neurological surgery patients: high-value care that bypasses the intensive care unit.

OBJECTIVE: High-value medical care is described as care that leads to excellent patient outcomes, high patient satisfaction, and efficient costs. Neurosurgical care in particular can be expensive for the hospital, as substantial costs are accrued during the operation and throughout the postoperative stay. The authors developed a "Safe Transitions Pathway" (STP) model in which select patients went to the postanesthesia care unit (PACU) and then the neuro-transitional care unit (NTCU) rather than being directly admitted to the neurosciences intensive care unit (ICU) following a craniotomy. They sought to evaluate the clinical and financial outcomes as well as the impact on the patient experience for patients who participated in the STP and bypassed the ICU level of care. METHODS: Patients were enrolled during the 2018 fiscal year (FY18; July 1, 2017, through June 30, 2018). The electronic medical record was reviewed for clinical information and the hospital cost accounting record was reviewed for financial information. Nurses and patients were given a satisfaction survey to assess their respective impressions of the hospital stay and of the recovery pathway. RESULTS: No patients who proceeded to the NTCU postoperatively were upgraded to the ICU level of care postoperatively. There were no deaths in the STP group, and no patients required a return to the operating room during their hospitalization (95% CI 0%-3.9%). There was a trend toward fewer 30-day readmissions in the STP patients than in the standard pathway patients (1.2% [95% CI 0.0%-6.8%] vs 5.1% [95% CI 2.5%-9.1%], p = 0.058). The mean number of ICU days saved per case was 1.20. The average postprocedure length of stay was reduced by 0.25 days for STP patients. Actual FY18 direct cost savings from 94 patients who went through the STP was $422,128. CONCLUSIONS: Length of stay, direct cost per case, and ICU days were significantly less after the adoption of the STP, and ICU bed utilization was freed for acute admissions and transfers. There were no substantial complications or adverse patient outcomes in the STP group.

Histopathologic findings in malignant peripheral nerve sheath tumor predict response to radiotherapy and overall survival.

BACKGROUND: Malignant peripheral nerve sheath tumor (MPNST) is an aggressive and poorly understood malignant neoplasm. Even in the setting of multimodal therapy, the clinical course of MPNST is frequently marked by metastatic conversion and poor overall prognosis, with optimal treatment paradigms for this rare tumor unknown. METHODS: We reviewed the medical records and histopathology of 54 consecutive patients who were treated at University of California San Francisco between 1990 and 2018. RESULTS: Our cohort consisted of 24 male and 30 female patients (median age 38 years). Fédération Nationale des Centres de Lutte Contre Le Cancer (FNCLCC) sarcoma grading criteria segregated patients into groups with differences in overall survival (OS) (P = .02). Increasing Ki-67 labeling index was associated with poor OS (hazard ratio [HR] 1.36 per 10%, P = .0002). Unsupervised hierarchical clustering-based immunohistochemical staining patterns identified 2 subgroups of tumors with differences in H3K27me3, Neurofibromin, S100, SOX10, p16, and EGFR immunoreactivity. In our cohort, cluster status was associated with improved locoregional failure-free rate (P = .004) in response to radiation. CONCLUSIONS: Our results lend support to the FNCLCC sarcoma grading criteria as a prognostic scheme for MPNST, although few cases of grade 1 were included. Further, we identify increased Ki-67 labeling as a strong predictor of poor OS from MPNST. Finally, we identify a subset of MPNSTs with a predictive immunohistochemical profile that has improved local control with adjuvant radiotherapy. These data provide insights into the grading and therapy for patients with MPNST, although further studies are needed for independent validation.

Schwannomatosis of the Spinal Accessory Nerve: A Case Report.

Schwannomatosis is a distinct syndrome characterized by multiple peripheral nerve schwannomas that can be sporadic or familial in nature. Cases affecting the lower cranial nerves are infrequent. Here, the authors present a rare case of schwannomatosis affecting the left spinal accessory nerve. Upon genetic screening, an in-frame insertion at codon p.R177 of the Sox 10 gene was observed. There were no identifiable alterations in NF1, NF2, LZTR1, and SMARCB1. This case demonstrates a rare clinical presentation of schwannomatosis in addition to a genetic aberration that has not been previously reported in this disease context.

Lumbar to sacral root rerouting to restore bladder function in a feline spinal cord injury model: Urodynamic and retrograde nerve tracing results from a pilot study.

AIMS: Lumbar to sacral rerouting surgery can potentially allow voiding via a skin-central nervous system-bladder reflex pathway. Here, we assessed if this surgery was effective in treating neurogenic bladder dysfunction/sphincter in felines. METHODS: Eight cats underwent spinal cord transection (SCT) at thoracic level 10/11. Unilateral L7 to S1 ventral root anastomosis was performed 1 month later in six cats. Two cats served as transection-only controls. Electrical and manual stimulation of L6-S1 dermatomes, and urodynamics were performed at 3, 5, 7, and 9/10 months post transection. At 9/10 months, cats were also evaluated by direct electrophysiological testing of anastomosed roots with urodynamics, then tissue collection and examination of the root anastomosis site and lumbosacral cord ventral horns for cells retrogradely labeled from tracer dye injected 2 weeks earlier into the bladder wall. RESULTS: At 9/10 months, four of six rerouted cats exhibited increased detrusor pressure provoked by cutaneous stimulation, one cat bilaterally. Two cats presented with a voiding stream after ipsilateral cutaneous stimulation at 7 and 9 months. All six rerouted animals showed regrowth of axons from the L7 ventral horn to the bladder, although some aberrant axonal regrowth was also observed. CONCLUSION: L7 to S1 ventral root rerouting below the level of SCT showed successful axonal regrowth to the bladder from the L7 spinal cord segment in all rerouted animals, and induced increased detrusor pressure response to cutaneous stimulation in a subset. This feasibility study paves the way for future animal studies for bladder reinnervation.

Rare Aggressive Calvarial Osteoblastoma with Dural Invasion.

We report a rare case of an aggressive osteoblastoma (OB) involving the calvaria and infiltrating the dura, a finding that was not previously reported in the literature. A 50-year-old man presented with a progressive mass in the left frontoparietal skull with headaches and a six-month history of sudden mass growth. Computed tomography (CT) and magnetic resonance imaging (MRI) showed a large skull lesion with areas of hemorrhage, calcification, restricted diffusion, and enhancement.  A left temporoparietal craniotomy with a complete resection of the tumor with grossly clean margins was performed. Follow-up at 60 months showed a stable clinical picture and no sign of local recurrence of the lesion on MRI.

Intrathecal catheter-associated inflammatory mass in a neurofibromatosis type-1 patient receiving fentanyl and bupivacaine.

BACKGROUND: Catheter-associated inflammatory masses (CIMs) are a rare but serious complication of intrathecal drug delivery devices. CIM formation is influenced by local medication concentration, which is determined in part by flow dynamics at the catheter tip. Underlying spinal pathologies, such as neoplasms, may alter flow at the catheter tip, thereby contributing to CIM formation. Moreover, they may also complicate the clinical and radiologic diagnosis of a CIM. CASE DESCRIPTION: A 36-year-old man with neurofibromatosis type 1 presented to our emergency department with complaints of increased back pain and leg weakness. To treat pain secondary to his multiple spinal masses, he had previously undergone placement of an implantable drug delivery system, which infused a compounded drug of fentanyl and bupivacaine. Imaging studies depicted numerous masses consistent with neurofibromatosis, including a compressive mass located circumferentially at the porous catheter terminus and proximal to the catheter tip. Surgical removal of this mass was performed; pathologic findings were consistent with a catheter tip granuloma. CONCLUSIONS: In the described case, CIM formation likely resulted from a combination of, 1) an unusually high fentanyl concentration, and, 2) altered infusate flow due to spinal neurofibromas. Consideration of underlying spinal pathologies, particularly mass lesions, is critical to the management of intrathecal drug delivery devices.

Rate of perioperative neurological complications after surgery for cervical spinal cord stimulation.

OBJECTIVE Cervical spinal cord stimulation (cSCS) is used to treat pain of the cervical region and upper extremities. Case reports and small series have shown a relatively low risk of complication after cSCS, with only a single reported case of perioperative spinal cord injury in the literature. Catastrophic cSCS-associated spinal cord injury remains a concern as a result of underreporting. To aid in preoperative counseling, it is necessary to establish a minimum rate of spinal cord injury and surgical complication following cSCS. METHODS The Nationwide Inpatient Sample (NIS) is a stratified sample of 20% of all patient discharges from nonfederal hospitals in the United States. The authors identified discharges with a primary procedure code for spinal cord stimulation (ICD-9 03.93) associated with a primary diagnosis of cervical pathology from 2002 to 2011. They then analyzed short-term safety outcomes including the presence of spinal cord injury and neurological, medical, and general perioperative complications and compared outcomes using univariate analysis. RESULTS Between 2002 and 2011, there were 2053 discharges for cSCS. The spinal cord injury rate was 0.5%. The rates of any neurological, medical, and general perioperative complications were 1.1%, 1.4%, and 11.7%, respectively. There were no deaths. CONCLUSIONS In the largest series of cSCS, the risk of spinal cord injury was higher than previously reported (0.5%). Nonetheless, this procedure remains relatively safe, and physicians may use these data to corroborate the safety of cSCS in an appropriately selected patient population. This may become a key treatment option in an increasingly opioid-dependent, aging population.

Large Cervical Vagus Nerve Tumor in a Patient with Neurofibromatosis Type 1 Treated with Gross Total Resection: Case Report and Review of the Literature.

Neurofibromas are benign peripheral nerve sheath tumors that occur commonly in individuals with neurocutaneous disorders such as neurofibromatosis type 1. Vagal nerve neurofibromas, however, are a relatively rare occurrence. We present the case of a 22-year-old man with neurofibromatosis type 1 with a neurofibroma of the left cervical vagal nerve. The mass was resected through an anterior approach without major event. In the postoperative course, the patient developed left vocal cord paralysis treated with medialization with injectable gel. We then present a comprehensive review of the literature for surgical resection of vagal nerve neurofibromas.

An algorithmic programming approach for back pain symptoms in failed back surgery syndrome using spinal cord stimulation with a multicolumn surgically implanted epidural lead: a multicenter international prospective study.

INTRODUCTION: Many studies have demonstrated the efficacy and the medical/economic value of epidural spinal cord stimulation for the treatment of "failed back surgery syndrome" (FBSS). However, the back pain component of FBSS has been recalcitrant. Recent clinical trials have suggested that multicolumn surgically implanted leads combined with enhanced programming capabilities in the newer implantable pulse generators demonstrate the ability to treat the back pain component of FBSS. The objective of our present international multicentre study is to prospectively evaluate these findings in a larger population. METHODS: We conducted a prospective, nonrandomized, observational study on 76 patients with refractory FBSS, consecutively implanted with multicolumn spinal cord stimulation (SCS) between 2008 and 2011 in three neurosurgical pain management centers (Poitiers, France; Montréal, Canada; and Regina, Canada). The primary objective of this study was to prospectively analyze the effect of multicolumn lead programming on paresthesia coverage for the back pain region in these patients. The secondary objective was to assess the analgesic efficacy of this technique on the global and back pain components. RESULTS: Paresthesia could be induced in the lower extremities in the majority of patients with at least one of the configurations tested. Bilateral low back paresthesia was induced in 53.5% of patients, while unilateral low back paresthesia was induced in 78.9% of patients. Multicolumn configurations were statistically more effective than monocolumn configurations for all anatomic regions studied. At 6 months, 75.4% of patients receiving multicolumn stimulation (n = 57) obtained at least a 30% improvement of the back pain VAS score, while 42.1% of patients obtained at least a 50% improvement of the back pain VAS score. CONCLUSION: This study confirms the hypothesis that multicolumn SCS should be considered as an important tool in the treatment of radicular and axial pain in FBSS patients. The efficacy of this modality is based on a rigorous patient selection process, access to new generation lead technologies, but most importantly an algorithmic programming approach for optimal stimulation and electrical field shaping. With over 40 million potential programming combinations associated with 16 contact leads to achieve paresthesia coverage, optimal stimulation is often missed as either the patient or the clinician become exhausted or overwhelmed during the course of therapy programming and optimization session.