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.

Characterization of Spinal Cord Injury Patients for Arm Functional Restoration through Nerve Transfer.

INTRODUCTION: Traumatic spinal cord injuries (tSCI) are common, often leaving patients irreparably debilitated. Therefore, novel strategies such as nerve transfers (NT) are needed for mitigating secondary SCI damage and improving function. Although different tSCI NT options exist, little is known about the epidemiological and injury-related aspects of this patient population. Here, we report such characteristics to better identify and understand the number and types of tSCI individuals who may benefit from NTs. MATERIALS AND METHODS: Two peripheral nerve experts independently evaluated all adult tSCI individuals < 80 years old admitted with cervical tSCI (C1-T1) between 2005 and 2019 with documented tSCI severity using the ASIA Impairment Scale for suitability for NT (nerve donor with MRC strength ≥ 4/5 and recipient ≤ 2/5). Demographic, traumatic injury, and neurological injury variables were collected and analyzed. RESULTS: A total of 709 tSCI individuals were identified with 224 (32%) who met the selection criteria for participation based on their tSCI level (C1-T1). Of these, 108 (15% of all tSCIs and 48% of all cervical tSCIs) were deemed to be appropriate NT candidates. Due to recovery, 6 NT candidates initially deem appropriate no longer qualified by their last follow-up. Conversely, 19 individuals not initially considered appropriate then become eligible by their last follow-up. CONCLUSION: We found that a large proportion of individuals with cervical tSCI could potentially benefit from NTs. To our knowledge, this is the first study to detail the number of tSCI individuals that may qualify for NT from a large prospective database.

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.

Foraminal Origin of the Dorsal Scapular Nerve: An Anatomical Study.

BACKGROUND: Although distal dorsal scapular nerve (DSN) anatomy has been well characterized, a paucity of literature exists detailing its proximal origin. To our knowledge, this is the first study examining DSN origin and its anatomy relative to the C5 nerve root, which may help localize pathology and provide insight into timing of DSN or C5 nerve root clinical and electrophysiological recovery. METHODS: Eighteen cadaveric dissections were performed using a posterior-midline approach. Calipers were used for DSN branching and course characterization with statistical analysis completed for the following measurements: DSN diameter, C5 nerve root diameter, distance of DSN branch-point from the C5 ganglion, dural edge, and posterior foraminal tubercle (intra-vs. extraforaminal origin), as well as C5 root-SC branch-point distance. RESULTS: Average/mean measurements (standard error) were as follows: DSN diameter: 3.7 mm (0.3 mm), C5 nerve root diameter: 6.2 mm (0.5 mm), DSN origin to C5 DRG: 12.4 mm (1.9 mm) distal, DSN origin to dural edge: 19. 6mm (1.8 mm), DSN origin to C5 root origin: 23.3 mm (2.2 mm), DSN origin to the posterior foraminal tubercle: 2.3 mm (2.5 mm) proximal/intraforaminal (first branch from C5 in all cases, and the majority [12 of 18, 67%] of DSNs originating from the C5 spinal nerve root within the foramen). CONCLUSIONS: The C5 nerve root contributed to the DSN in all specimens that originated from the proximal, intraforaminal, C5 nerve root in the majority of specimens. As the first C5 nerve branch, surgeon knowledge of this proximal DSN pattern will help localize lesional pathology, as well as may help monitor clinical and electrophysiological recovery.

Foraminal Ligaments Tether Upper Cervical Nerve Roots: A Potential Cause of Postoperative C5 Palsy.

Background Nerve root tethering upon dorsal spinal cord (SC) migration has been proposed as a potential mechanism for postoperative C5 palsy (C5P). To our knowledge, this is the first study to investigate this relationship by anatomically comparing C5-C6 nerve root translation before and after root untethering by cutting the cervical foraminal ligaments (FL). Objective The aim of this study is to determine if C5 root untethering through FL cutting results in increased root translation. Methods Six cadaveric dissections were performed. Nerve roots were exposed via C4-C6 corpectomies and supraclavicular brachial plexus exposure. Pins were inserted into the C5-C6 roots and adjacent foraminal tubercle. Translation was measured as the distance between pins after the SC was dorsally displaced 5 mm before and after FL cutting. Clinical feasibility of FL release was examined by comparing root translation between standard and extended (complete foraminal decompression) foraminotomies. Translation of root levels before and after FL cutting was compared by two-way repeated measures analysis of variance. Statistical significance was set at 0.05. Results Significantly more nerve root translation was observed if the FL was cut versus not-cut, p = 0.001; no difference was seen between levels, p = 0.33. Performing an extended cervical foraminotomy was technically feasible allowing complete FL release and root untethering, whereas a standard foraminotomy did not. Conclusion FL tether upper cervical nerve roots in their foramina; cutting these ligaments untethers the root and increases translation suggesting they could be harmful in the context of C5P. Further investigation is required examining the value of root untethering in the context of C5P.

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.

Ultrasound for Neurogenic Thoracic Outlet Obstruction Remains Theoretical.

We enjoyed reading Povleson et al.'s review entitled "Diagnostic thoracic outlet syndrome: current approaches and future directions" [...].

Radiological data of brachial plexus avulsion injury associated spinal cord herniation (BPAI-SCH) and comparison to anterior thoracic spinal cord herniation (ATSCH).

Spinal cord herniation (SCH) is a rare cause of myelopathy. When reported, SCH has most commonly been described as occurring spontaneously in the thoracic spine, and being idiopathic in nature (anterior thoracic spinal cord herniation, ATSCH) [1-3]. Several theories have been proposed to explain its occurrence, including congenital, inflammatory, and traumatic etiologies alike [1-4]. Even more rarely, SCH has been described to occur in the cervical spine in association with brachial plexus avulsion injuries (BPAI-SCH). In our accompanying article, "Late Cervical Spinal Cord Herniation Resulting from Post-Traumatic Brachial Plexus Avulsion Injury," two cases of BPAI-SCH are presented and discussed in the context of the reviewed literature [5]. Here, pertinent accompanying follow-up data was collected and is presented for the cases, including postoperative radiographic outcome imaging. Furthermore, a table is presented comparing and contrasting ATSCH to BPAI-SCH. Although the two phenomena have been previously grouped together, this table highlights ATSCH and BPAI-SCH as distinct entities; more specifically, BPAI-SCH is a separate, long-term complicating feature of BPAI. This supplementary data helps treating physicians by increasing awareness and knowledge of BPAI-SCH as a distinct entity from ATSCH and cause of delayed neurological deterioration.

Late Cervical Spinal Cord Herniation Resulting from Post-Traumatic Brachial Plexus Avulsion Injury.

BACKGROUND: Spinal cord herniation (SCH) is often described as occurring spontaneously in the thoracic spine, with few cases of cervical SCH reported as a late complication of traumatic brachial plexus avulsion. We present 2 cases of nerve root avulsion and pseudomeningocele formation, resulting in delayed cervical SCH and neurologic deterioration. CASE DESCRIPTION: Case 1: A 37-year old man presented with progressive leg weakness 2 years after experiencing traumatic C8 and T1 root avulsions. Magnetic resonance imaging (MRI) showed previously documented C8-T1 nerve avulsions with new SCH in a T1 pseudomeningocele. A C7-T1 costotransversectomy and C4-T4 instrumented fusion were completed, allowing SCH reduction and patch graft repair of the dural defects without the need for adhesiolysis. At last follow-up, the patient's leg weakness had resolved. Case 2: A 32-year old man presented with progressive right arm numbness, weakness, and signs of myelopathy 9 years after experiencing C8 and T1 root avulsions. MRI showed previously documented root avulsions and new SCH with extensive and compressive pseudomeningocele formation. A C7 transpedicular approach with C5-T1 instrumented fusion was completed for dural repair. A large pseudomeningocele was found and drained on drilling the C7 pedicle, and adhesiolysis was required at the spinal cord avulsion site to reduce the SCH and allow patch graft repair. At last follow-up, the patient's right arm weakness was improving, although numbness persisted. CONCLUSIONS: SCH is a rare cause of delayed neurologic deterioration after brachial plexus avulsion, with few case reports describing its occurrence. We present 2 cases of this complication and describe its successful surgical treatment through dural repair after instrumented fusion.

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.