Clinical Research Primer for Medical Students: Overview and Illustrative Experiences.

Background The ability to participate in clinical scholarship is a foundational component of modern evidence-based medical practice, empowering improvement across essentially every aspect of clinical care. In tandem, the need for comprehensive exposure to clinical research has been identified as a critical component of medical student training and preparation for residency that is underserved by traditional undergraduate medical education models. The goal of the current work was to provide guidelines and recommendations to assist novice medical students in taking ownership of their research education. Methods The Clinical Research Primer was composed from pooled research documents compiled by the study authors and our institutional neurosurgery student research group. The Primer was then structured as the natural evolution of a research project from its inception through the submission process. Results We divided the foundational components of the Clinical Research Primer into seven domains, each representing a landmark in the development of a peer-reviewed study, and a set of skills critical for junior scholars to develop. These vital components included the following: pitching and designing clinical studies, developing a research workflow, navigating the Institutional Review Board, data collection and analysis, manuscript writing and editing, submission mechanics, and tracking research projects for career development. Conclusion We anticipate that the tools included in the Clinical Research Primer will increase student research productivity and preparedness for residency. Although our recommendations are informed by our experiences within neurosurgery, they have been written in a manner that should generalize to almost any field of clinical study.

Specific gene expression signatures of low grade meningiomas.

Introduction: Meningiomas are the most common primary central nervous system (CNS) tumors in adults, representing approximately one-third of all primary adult CNS tumors. Although several recent publications have proposed alternative grading systems of meningiomas that incorporate genomic and/or epigenomic data to better predict meningioma recurrence and progression-free survival, our understanding of driving forces of meningioma development is still limited. Objective: To define gene expression signatures of the most common subtypes of meningiomas to better understand cellular processes and signaling pathways specific for each tumor genotype. Methods: We used RNA sequencing (RNA-seq) to determine whole transcriptome profiles of twenty meningiomas with genomic alterations including NF2 inactivation, loss of chr1p, and missense mutations in TRAF7, AKT1 and KLF4. Results: The analysis revealed that meningiomas with NF2 gene inactivation expressed higher levels of BCL2 and GLI1 compared with tumors harboring TRAF7 missense mutations. Moreover, NF2 meningiomas were subdivided into two distinct groups based on additional loss of chr1p. NF2 tumors with intact chr1p were characterized by the high expression of tumor suppressor PTCH2 compared to NF2 tumors with chr1p loss. Taken together with the high expression of BCL2 and GLI1, these results suggest that activation of Sonic Hedgehog pathway may contribute to NF2 meningioma development. In contrast, NF2 tumors with chr1p loss expressed high levels of transcription factor FOXD3 and its antisense RNA FOXD3-AS1. Examination of TRAF7 tumors demonstrated that TRAF7 regulates a number of biomechanically responsive genes (KRT6a, KRT16, IL1RL1, and AQP3 among others). Interestingly, AKT1 and KLF4 meningiomas expressed genes specific for PI3K/AKT signaling pathway, suggesting overlapping gene signatures between the two subtypes. In addition, KLF4 meningiomas had high expression of carcinoembryonic antigen family members CEACAM6 and CEACAM5. Conclusions: Each group of meningiomas displayed a unique gene expression signature suggesting signaling pathways potentially implicated in tumorigenesis. These findings will improve our understanding of meningioma tumorigenesis and prognosis.

Patient Outcomes in Disorders of Consciousness Following Transcranial Magnetic Stimulation: A Systematic Review and Meta-Analysis of Individual Patient Data.

Background: There are few treatments with limited efficacy for patients with disorders of consciousness (DoC), such as minimally conscious and persistent vegetative state (MCS and PVS). Objective: In this meta-analysis of individual patient data (IPD), we examine studies utilizing transcranial magnetic stimulation (TMS) as a treatment in DoC to determine patient and protocol-specific factors associated with improved outcomes. Methods: We conducted a systematic review of PubMed, Ovid Medline, and Clinicaltrials.gov through April 2020 using the following terms: "minimally conscious state," or "persistent vegetative state," or "unresponsive wakefulness syndrome," or "disorders of consciousness" and "transcranial magnetic stimulation." Studies utilizing TMS as an intervention and reporting individual pre- and post-TMS Coma Recovery Scale-Revised (CRS-R) scores and subscores were included. Studies utilizing diagnostic TMS were excluded. We performed a meta-analysis at two time points to generate a pooled estimate for absolute change in CRS-R Index, and performed a second meta-analysis to determine the treatment effect of TMS using data from sham-controlled crossover studies. A linear regression model was also created using significant predictors of absolute CRS-R index change. Results: The search yielded 118 papers, of which 10 papers with 90 patients were included. Patients demonstrated a mean pooled absolute change in CRS-R Index of 2.74 (95% CI, 0.62-4.85) after one session of TMS and 5.88 (95% CI, 3.68-8.07) at last post-TMS CRS-R assessment. The standardized mean difference between real rTMS and sham was 2.82 (95% CI, -1.50 to 7.14), favoring rTMS. The linear regression model showed that patients had significantly greater CRS-R index changes if they were in MCS, had an etiology of stroke or intracranial hemorrhage, received 10 or more sessions of TMS, or if TMS was initiated within 3 months from injury. Conclusions: TMS may improve outcomes in MCS and PVS. Further evaluation with randomized, clinical trials is necessary to determine its efficacy in this patient population.

Reported incidence and treatment modalities of giant cerebral aneurysms in the pediatric population: A systematic review and illustrative case report.

Giant intracranial aneurysms represent a complex pathology that pose challenges for management, especially in the pediatric population. With emerging endovascular techniques, combined endovascular and open surgical approaches may be a favorable alternative for complex cases. In this systematic review, we characterize the treatment modalities of giant aneurysms in the pediatric population and provide an update on the number of giant aneurysms reported in the literature by anatomic location. We conducted a literature search of PubMed, Embase, and Medline databases with the following terms: 'pediatric' AND 'giant' AND 'intracranial aneurysm.' Studies were included if data on treatment modality and aneurysm location were available for pediatric patients with giant intracranial aneurysms. The literature search yielded a total of 188 papers, with 82 pediatric patients from 33 articles ultimately meeting inclusion criteria. There were significantly more male than female patients (p = 0.011), with 52 and 29 respectively. Patients presenting with a ruptured aneurysm were significantly younger than patients presenting without rupture (p = 0.018), with a median age of 8.0 and 12.0 years, respectively. There were 45 giant aneurysms reported in the anterior circulation and 37 in the posterior circulation. Anterior aneurysms were most often treated with surgical approaches, while posterior aneurysms were typically treated with endovascular interventions (p = 0.002). Although combined surgical and endovascular approaches were the least frequently utilized, we suggest a combined approach may be particularly useful for patients with complex cases that require a management plan tailored to their needs.

Dynamic Occlusion of Distal Ventriculoperitoneal Shunt Catheter after Infusion Port Placement: A New Shunt Malfunction.

Shunt failure requiring reintervention remains a common complication of hydrocephalus treatment. Here, we report a novel cause of mechanical shunt obstruction in an adult patient: position-dependent intermittent occlusion via an infusion port catheter. A 51-year-old woman with a grade II oligodendroglioma presented in a delayed fashion following surgery with a pseudomeningocele. She underwent ventriculoperitoneal shunt placement due to communicating hydrocephalus, resolving her pseudomeningocele. Shortly thereafter, she underwent placement of a subclavian infusion port at an outside institution. Her pseudomeningocele returned. Imaging demonstrated close proximity of her port catheter to the shunt catheter overlying the clavicle. Her shunt was tapped demonstrating a patent ventricular catheter with normal pressure. She underwent shunt exploration after her pseudomeningocele did not respond to valve adjustment. Intraoperative manometry demonstrated head position-dependent distal catheter obstruction. Repeat manometry following distal catheter revision demonstrated normal runoff independent of position. Her pseudomeningocele was resolved on follow-up. To our knowledge, this is the only reported case of intermittent, position-dependent distal catheter obstruction. Shunted patients with concern for malfunction following subclavian infusion port placement should be evaluated for possible dynamic obstruction of their distal catheter when the two catheters are in close proximity along the clavicle.

Akinetic mutism reversed by inferior parietal lobule repetitive theta burst stimulation: Can we restore default mode network function for therapeutic benefit?

BACKGROUND: Transcranial magnetic stimulation is a noninvasive treatment used to modulate cortical excitability. Its use over the last two decades has expanded, ranging from psychiatric disorders to traumatic brain injury and poststroke rehabilitation. OBJECTIVES: We present the case of a 59-year-old male patient who presented in a decreased state of consciousness due to a right frontal glioblastoma, wherein his state was not improved by a successful surgery and could not be explained by any other condition. Due to his poor prognosis, we examine the benefits of receiving transcranial magnetic stimulation treatment to improve his akinetic mutism. METHODS: We utilized independent component analysis with resting-state functional magnetic resonance imaging (rsfMRI) to better understand his cortical functionality. The imaging suggested absence of the default mode network (DMN). The patient underwent five sessions of navigated intermittent theta burst stimulation to the ipsilesional inferior parietal lobule and inferior frontal gyrus, with the aim of improving his default mode network functionality. RESULTS: No other treatments resulted in an improvement of this patient's condition; however, 3 weeks following transcranial magnetic stimulation treatment, the patient was more alert and interactive, and his follow-up rsfMRI scan demonstrated a partially intact default mode network. CONCLUSION: This case raises important questions regarding the clinical utility of transcranial magnetic stimulation to improve the connectivity of important cerebral networks and subsequent related functional recovery.

Venous Sinus Stenosis Treatment in Pediatric Idiopathic Intracranial Hypertension: Illustrative Case and Literature Review.

OBJECTIVE: To review the literature of venous sinus stenosis (VSS) treatment in children for idiopathic intracranial hypertension (IIH) and present our own institutional case. METHODS: A literature review was conducted using the PubMed and MEDLINE databases up to June 2020. From 134 studies that were screened, 6 studies were chosen for analysis that included patients <18 years old, a diagnosis of IIH that fit Dandy diagnostic criteria, and angiogram obtained to assess for VSS. IIH symptoms experienced in the pediatric population and efficacy of venous sinus stenting were analyzed. RESULTS: Eleven patients identified in the literature and 1 patient from our institution were included in the analysis. There was no statistically significant difference in pressure gradient response to stenting between male and female patients (P = 0.424) or patients with body mass index >90th percentile (P = 0.626). Larger decreases in pressure gradient after stent placement correlated with headache resolution (P = 0.0005). Patients who underwent unilateral stenting showed greater reduction in pressure gradient compared with patients who underwent bilateral stenting (average change 24 mm Hg vs. 5.75 mm Hg, P = 0.003). CONCLUSIONS: Our analysis showed that VSS treatment has the potential to be a safe option for IIH in pediatric patients. VSS treatment has shown similar results to traditional cerebrospinal fluid diversion procedures, with a lower complication rate and need for revision. More studies should be conducted to analyze the long-term efficacy and safety of VSS treatment in pediatric patients with IIH.

Navigated transcranial magnetic stimulation following awake craniotomy for resection of glioma: Description of two cases.

BACKGROUND: Although transcranial magnetic stimulation (TMS) has been indicated as a potential therapy for several neurologic conditions, there is little known regarding its use during the postoperative rehabilitation period in patients with brain tumors. Furthermore, seizures, a common presentation in these patients, are regarded as a major contraindication for TMS therapy. CASE DESCRIPTION: We demonstrate that postoperative continuous theta burst stimulation (cTBS), a patterned form of repetitive TMS, was safely tolerated in addition to current neurorehabilitation techniques in two brain tumor patients, including one patient with a history of tumor-related epilepsy. We administered navigated 5 Hz cTBS to two patients within 48 h following awake craniotomy for tumor resection. Active motor thresholds were measured in both patients before TBS administration to determine stimulus intensity. We used resting-state fMRI to identify likely damaged networks based on postoperative deficits. This aided in TMS planning and allowed deficit targeted therapy contralateral to the lesioned network node. Both patients tolerated TBS therapy well and had no adverse effects, including posttreatment seizures, despite one patient having a history of tumor-related epilepsy. CONCLUSION: TBS may be safe in the immediate postoperative period for patients following brain tumor resection. Additional studies are needed to quantify the efficacy of TMS in improving neurologic deficits following tumor resection.