Sleep Symptoms in Migraine.

PURPOSE OF REVIEW: To review replicated and highlight novel studies of sleep in children and adults with episodic and chronic migraine. RECENT FINDINGS: Attack-related sleep symptoms are most common in the prodrome and may represent early activation of the hypothalamus rather than migraine triggers. Interictally, patients with migraine report poor sleep quality and high rates of insomnia symptoms. Cognitive behavioral therapy for insomnia in adults and adolescents with chronic migraine and comorbid insomnia results in significant improvement on their headache burden. Thus far, objective studies report that migraine per se is a not associated with sleep apnea. At the present time, there is minimal evidence that migraine is under circadian influence. The current body of evidence suggests that the insomnia symptoms and poor sleep quality commonly reported by patients with migraine are not attack-related but occur interictally and are a marker of worsening disease. The development of clinical guidelines to approach sleep symptoms and expansion of CBT-I trials in those with episodic migraine would be clinically valuable.

Tumor-specific polycistronic miRNA delivered by engineered exosomes for the treatment of glioblastoma.

BACKGROUND: Glioblastoma (GBM) has poor prognosis due to ineffective agents and poor delivery methods. MicroRNAs (miRs) have been explored as novel therapeutics for GBM, but the optimal miRs and the ideal delivery strategy remain unresolved. In this study, we sought to identify the most effective pan-subtype anti-GBM miRs and to develop an improved delivery system for these miRs. METHODS: We conducted an unbiased screen of over 600 miRs against 7 glioma stem cell (GSC) lines representing all GBM subtypes to identify a set of pan-subtype-specific anti-GBM miRs and then used available TCGA GBM patient outcomes and miR expression data to hone in on miRs that were most likely to be clinically effective. To enhance delivery and expression of the miRs, we generated a polycistronic plasmid encoding 3 miRs (pPolymiR) and used HEK293T cells as biofactories to package pPolymiR into engineered exosomes (eExos) that incorporate viral proteins (Gag/VSVg) in their structure (eExos+pPolymiR) to enhance function. RESULTS: Our stepwise screen identified miR-124-2, miR-135a-2, and let-7i as the most effective miRs across all GBM subtypes with clinical relevance. Delivery of eExos+pPolymiR resulted in high expression of all 3 miRs in GSCs, and significantly decreased GSC proliferation in vitro. eExos+pPolymiR prolonged survival of GSC-bearing mice in vivo when compared with eExos carrying each of the miRs individually or as a cocktail. CONCLUSION: eExos+pPolymiR, which includes a pan-subtype anti-glioma-specific miR combination encoded in a polycistronic plasmid and a novel exosome delivery platform, represents a new and potentially powerful anti-GBM therapeutic.

An immune-competent, replication-permissive Syrian Hamster glioma model for evaluating Delta-24-RGD oncolytic adenovirus.

BACKGROUND: Oncolytic adenoviruses are promising new treatments against solid tumors, particularly for glioblastoma (GBM), and preclinical models are required to evaluate the mechanisms of efficacy. However, due to the species selectivity of adenovirus, there is currently no single animal model that supports viral replication, tumor oncolysis, and a virus-mediated immune response. To address this gap, we took advantage of the Syrian hamster to develop the first intracranial glioma model that is both adenovirus replication-permissive and immunocompetent. METHODS: We generated hamster glioma stem-like cells (hamGSCs) by transforming hamster neural stem cells with hTERT, simian virus 40 large T antigen, and h-RasV12. Using a guide-screw system, we generated an intracranial tumor model in the hamster. The efficacy of the oncolytic adenovirus Delta-24-RGD was assessed by survival studies, and tumor-infiltrating lymphocytes (TILs) were evaluated by flow cytometry. RESULTS: In vitro, hamGSCs supported viral replication and were susceptible to Delta-24-RGD mediated cell death. In vivo, hamGSCs consistently developed into highly proliferative tumors resembling high-grade glioma. Flow cytometric analysis of hamster gliomas revealed significantly increased T-cell infiltration in Delta-24-RGD infected tumors, indicative of immune activation. Treating tumor-bearing hamsters with Delta-24-RGD led to significantly increased survival compared to hamsters treated with phosphate buffered saline (PBS). CONCLUSIONS: This adenovirus-permissive, immunocompetent hamster glioma model overcomes the limitations of previous model systems and provides a novel platform to study the interactions between tumor cells, the host immune system, and oncolytic adenoviral therapy; understanding of which will be critical to implementing oncolytic adenovirus in the clinic.

Intracranial Solitary Fibrous Tumor of the Skull Base: 2 Cases and Systematic Review of the Literature.

BACKGROUND: Intracranial solitary fibrous tumors (ISFTs) are rare neoplasms of mesenchymal origin that originate from the meninges. ISFTs of the skull base can be challenging to treat, as resection can be complicated by skull base anatomy. We present 2 cases of ISFT, the first manifesting with compressive cranial neuropathy from Meckel cave involvement and the second a posterior fossa lesion causing symptomatic hydrocephalus. METHODS: A systematic review was performed according to Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. The PubMed database was queried with title/abstract keywords "intracranial," "solitary fibrous tumor," "hemangiopericytoma," "SFT," and "HPC." Search results were reviewed to exclude cases not involving the skull base. References from all selected articles were reviewed for potential additional cases. Patient demographic and clinical data from 58 identified skull base cases were collected for qualitative synthesis. RESULTS: Visual disturbances were the most common presenting symptom (30 cases, 52%) followed by headache (22 cases, 38%). The most common site of involvement was the sellar/parasellar region (18 cases, 31%) followed by middle fossa/temporal bone (14 cases, 24%). Resection was performed in 55 cases; gross total resection was reported in 26 cases (45%) and subtotal resection was reported in 21 cases (36%). Tumor recurrence was documented in 15 cases (26%) with median and mean follow-up periods of 16 and 29.9 months, respectively. CONCLUSIONS: We discuss presentation, imaging, histopathology, and management considerations for ISFTs while highlighting the potentially complex nature of skull base lesions and need for multidisciplinary approach to treatment.

Spinal meningioma in a patient with multiple sclerosis.

BACKGROUND: Multiple sclerosis (MS) is the most common immune-mediated inflammatory demyelinating disease of the central nervous system. Multiple brain and spinal tumors have been linked to MS, but a causal relationship between the two has not been determined. Here, we report a case of spinal meningioma in a patient with MS and review literature discussing the possible connection between these two disease entities. CASE DESCRIPTION: A 58-year-old female with MS presented with a 1-year history of progressively worsening back pain in conjunction with worsening right upper and lower extremity weakness. The patient was diagnosed with MS 19 months prior and had multiple known demyelinating plaques in her cervical spine. New MRI revealed an intradural extramedullary thoracic tumor with characteristics consistent with meningioma. She underwent T6- T8 laminectomies for tumor resection and pathology confirmed the radiological diagnosis. At 3-month follow- up, the patient reported complete resolution of her back pain and persistence of weakness-related gait issues. CONCLUSION: CNS neoplasms including meningioma should be considered in MS patients presenting with newly onset neurological symptoms not entirely consistent with demyelinating disease. Both disease processes should be addressed with appropriate long-term follow-up.

Novel use of a double lumen balloon catheter for venous sinus thrombolysis and venoplasty.

We describe the novel use of a double lumen balloon catheter for venous sinus thrombolysis and venoplasty. Cerebral venous sinus thrombosis is a rare disease that is usually treated with medical anticoagulation. In certain refractory cases, surgical or endovascular thrombolysis and thrombectomy may be required. A 48 year-old man on anticoagulation for cerebral venous sinus thrombosis presented with nausea, vomiting and worsening hemiparesis. The patient underwent endovascular venous sinus thrombolysis and venoplasty with continuous in situ tissue plasminogen activator (tPA) infusion over 48 hours. This novel approach to the endovascular treatment of venous sinus thrombosis, including the use of a double lumen balloon was advantageous, as it allowed direct infusion of tPA through the balloon catheter without having to exchange the balloon for a microcatheter.

A pilot study to assess the construct and face validity of the Northwestern Objective Microanastomosis Assessment Tool.

OBJECT: Microsurgical skills remain an integral component of neurosurgical education. There is a need for an objective scale to assess microsurgical skills. The objective of this study was to assess the face and construct validity of a bench training microanastomosis module and an objective assessment scale, i.e., the Northwestern Objective Microanastomosis Assessment Tool (NOMAT). METHODS: Medical students, neurosurgical residents, and postdoctoral research fellows at Northwestern University were enrolled in the study. Trainees were divided into 3 groups based on microsurgical experience: 1) experienced, 2) exposed, and 3) novices. Each trainee completed two end-to-end microanastomoses using a 1-mm and a 3-mm synthetic vessel. Two cameras were installed to capture procedural footage. One neurosurgeon blindly graded the performance of trainees using both objective and subjective methods to assess construct validity. Two neurosurgeons reviewed the contents of the simulation module to assess face validity. RESULTS: Twenty-one trainees participated in the study, including 6 experienced, 6 exposed, and 9 novices. The mean NOMAT score for experienced trainees on the 1-mm module was 47.3/70 compared with 26.0/70 and 25.8/70 for exposed and novice trainees, respectively (p = 0.02). Using subjective grading, experienced trainees performed significantly better on the 1-mm module (64.2/100) compared with exposed or novice trainees (23.3/100 and 25.0/100, respectively; p = 0.02). No statistical difference between groups was noted for the 3-mm module with both NOMAT and subjective grading. Experienced trainees took less time to perform both tasks compared with the others. CONCLUSIONS: Face and construct validities of the microanastomosis module were established. The scale and the microanastomosis module could help assess the microsurgical skills of neurosurgical trainees and serve as a basis for the creation of a microsurgical curriculum.

Intracranial aneurysms in previously irradiated fields: literature review and case report.

OBJECTIVE: Radiotherapy is a common treatment for a variety of disease processes in the central nervous system; it has an ever-increasing number of indications and applications. With the life expectancy of cancer patients increasing, delayed complications of radiation have become more apparent. One such potential complication is the appearance of intracranial aneurysms in the irradiated field. The incidence and natural history of these aneurysms is not well understood. To this end, we performed a review of the literature to analyze the current state of knowledge of these rare aneurysms. Furthermore, we present a case treated at our center. METHODS: We reviewed the literature for all reported cases of intracranial aneurysms appearing in an irradiated field, including any available histopathologic analysis. All papers were included irrespective of the language in which it was published. We calculated the mean age at radiation exposure, the interval between radiation exposure, and aneurysm development and the rate of presentation. Herein we also present a case of an intracranial aneurysm in a 38-year-old patient detected in an irradiation field 33 years after the patient underwent craniospinal irradiation for a medulloblastoma. RESULTS: A total of 46 patients with 69 intracranial aneurysms in irradiation fields were reported between 1978 and 2013. The mean age at radiation exposure was 34 years, and the mean lag time between exposure and diagnosis was 12 years (range, 4 months to 50 years). The median lag time between exposure and diagnosis was shorter in patients older than 40 (6 years). Among the reported aneurysms, 83% were saccular, 9% were fusiform, and 9% were considered pseudo-aneurysms. The Median lag time was 20 years for brachytherapy, 8 years for focused radiation, 9 years for whole brain radiation, and 6 years for SRS. Among reported aneurysms, 55% presented with some form of hemorrhage: intracranial rupture with subarachnoid hemorrhage, epistaxis, or otorrhagia. Only 13% were discovered on routine follow-up or were found incidentally for work-up of unrelated neurologic symptoms. CONCLUSION: Although rarely reported, intracranial aneurysms in irradiation fields may warrant special attention when diagnosed. These aneurysms may have an inherently weaker structure and may be more prone to rupture. Their repair may also be complicated by more fragile and irregular morphology. The increasing longevity of cancer patients suggests that screening for aneurysms at irradiation sites may be warranted, but further studies are needed to validate this approach.

A didactic and hands-on module enhances resident microsurgical knowledge and technical skill.

BACKGROUND: Simulation has been adopted as a powerful training tool in many areas of health care. However, it has not yet been systematically embraced in neurosurgery because of the absence of validated tools, assessment scales, and curricula. OBJECTIVE: To use our validated microanastomosis module and scale to evaluate the effects of an educational intervention on the performance of neurosurgery residents at the 2012 Congress of Neurological Surgeons Annual Meeting. METHODS: The module consisted of an end-to-end microanastomosis of a 3-mm vessel and was divided into 3 phases: (1) a cognitive and microsuture prelecture testing phase, (2) a didactic lecture, and (3) a cognitive and microsuture postlecture testing phase. We compared resident knowledge and technical proficiency from the pretesting and posttesting phases. RESULTS: One neurosurgeon and 7 neurosurgery residents participated in the study. None had previous experience in microsurgery. The average score on the microsuture prelecture and postlecture tests, as measured by our assessment scale, was 32.50 and 39.75, respectively (P = .001). The number of completed sutures at the end of each procedure was higher for 75% of participants in the postlecture testing phase (P = .03). The average score on the cognitive postlecture test (12.75) was significantly better than that of the cognitive prelecture test (8.38; P = .001). CONCLUSION: Simulation has the potential to enhance resident education and to elevate proficiency levels. Our data suggest that a focused microsurgical module that incorporates a didactic component and a technical component can enhance resident knowledge and technical proficiency in microsurgical anastomosis.

New-generation oral anticoagulants for the prevention of stroke: implications for neurosurgery.

A new generation of oral anticoagulants, namely direct thrombin inhibitors and factor Xa inhibitors, have recently been approved for clinical use in patients with atrial fibrillation. These novel families of drugs have been shown to have favorable efficacy and safety profiles in multiple clinical settings, particularly in the prevention of atrial fibrillation-related stroke, and are likely to become part of everyday practice, making a crossover to neurosurgical patients inevitable. Concern has risen regarding the complexity of managing intracranial and intraspinal hemorrhages related to these drugs. This review aims to provide an update on the most recent advances in oral anticoagulant drug therapy from a neurosurgeon's perspective. We discuss current evidence for the use of these novel agents, their limitations, existing methods of drug-level monitoring, and controversies related to anticoagulation reversal. We also discuss specific topics such as anticoagulation resumption after intracranial or intraspinal bleeding, perioperative anticoagulant administration, and the possibility of combination with tissue plasminogen activator in the setting of acute ischemic stroke. A special focus is given to the incidence of intracranial and intraspinal hemorrhage associated with each drug.

Surgical treatment of elevated intracranial pressure: decompressive craniectomy and intracranial pressure monitoring.

Surgical techniques that address elevated intracranial pressure include (1) intraventricular catheter insertion and cerebrospinal fluid drainage, (2) removal of an intracranial space-occupying lesion, and (3) decompressive craniectomy. This review discusses the role of surgery in the management of elevated intracranial pressure, with special focus on intraventricular catheter placement and decompressive craniectomy. The techniques and potential complications of each procedure are described, and the existing evidence regarding the impact of these procedures on patient outcome is reviewed. Surgical management of mass lesions and ischemic or hemorrhagic stroke occurring in the posterior fossa is not discussed herein.

The role of simulation in neurosurgical education: a survey of 99 United States neurosurgery program directors.

OBJECTIVE: With the reduction of resident work hours and the increasing focus on patient safety, it has become evident that simulation has a growing role to play in surgical education. We surveyed the program directors of 99 U.S. Neurosurgery programs in an effort to better understand how simulation can be implemented in Neurosurgery and to gain insight into key issues that are currently being discussed amongst Neurosurgical educators. METHODS: A 14-item questionnaire was emailed to 99 Neurosurgery residency program directors. Questions assessed the clinical impact of simulation, the role of simulation in academia, the investments required in time and money, and the model best suited for simulation. RESULTS: The survey response rate was 53.5%. Seventy-two percent of respondents believed that simulation would improve patient outcome, 74% that it could supplement conventional training, but only 25% that it could replace it. The majority strongly believed that it could help preparing complex cases and could be of use to attending faculty. Forty-five percent thought that residents should achieve pre-defined levels of proficiency on simulators before working on patients. Seventy-four percent of respondents declared they would make simulator practice mandatory if available, and the majority was willing to invest daily time and considerable funds on simulators. Cadavers were the least preferred models to use compared to virtual simulation and noncadaveric physical models. CONCLUSIONS: Simulation should be integrated in Neurosurgery training curricula. The validation of available tools is the next step that will enable the training, acquisition, and testing of neurosurgical skills.

De novo large fusiform posterior circulation intracranial aneurysm presenting with subarachnoid hemorrhage 7 years after therapeutic internal carotid artery occlusion: case report and review of the literature.

BACKGROUND AND IMPORTANCE: Although the use of proximal artery occlusion, or hunterian ligation, for the treatment of intracranial aneurysms has decreased greatly over the past decades, this approach still finds use for certain giant and complex aneurysms. The main risks of artery sacrifice are ischemic complications but also, although rare, de novo aneurysm formation. We present here a case of de novo formation of a large fusiform basilar artery aneurysm 7 years after internal carotid artery occlusion. CLINICAL PRESENTATION: A 17-year-old male patient with a history of a giant right cavernous aneurysm treated 7 years earlier with right-sided endovascular internal carotid artery occlusion presented to our institution with a thunderclap headache. At the time of initial evaluation, the patient was neurologically intact and imaging revealed a 22 × 10-mm fusiform aneurysm of the distal basilar artery with mass effect on the adjacent pons as well as a small amount of subarachnoid and intraventricular blood. Complete occlusion of the right internal carotid artery was demonstrated with retrograde filling of the right middle cerebral artery from the enlarged right posterior communicating artery. The patient was subsequently treated with hunterian occlusion of the basilar artery below anterior inferior cerebellar arteries. A superficial temporal artery to middle cerebral artery bypass was performed on the right side before this occlusion. CONCLUSION: Further studies on the epidemiology of de novo aneurysms after carotid artery occlusion are warranted. Patients at higher risk of the development of intracranial aneurysms should be followed aggressively after hunterian ligation, and the possibility of an extracranial-intracranial bypass should be discussed.

Surgical and endovascular treatments for intracranial aneurysms.

The goals of microsurgical and endovascular treatment of intracranial aneurysms are to prevent subarachnoid hemorrhage and/or eliminate mass effect symptoms. Debate has raged regarding which aneurysms to treat and with which technique or combination of techniques. It is our impression that studies that have assessed aneurysm natural history and treatment options are compromised by the inherent limitations of clinical trials, with many natural history studies likely underestimating rupture risk over long-term follow-up. Endovascular therapy and open neurosurgery should both be used strategically, and our current interest is in integrating these techniques in a fashion extending beyond the simplistic clip-versus-coil debate.