Magnetic Resonance Imaging of Mouse Cerebral Cavernomas Reveal Differential Lesion Progression and Variable Permeability to Gadolinium.

BACKGROUND: Cerebral cavernous malformations, also known as cavernous angiomas, are blood vessel abnormalities comprised of clusters of grossly enlarged and hemorrhage-prone capillaries. The prevalence in the general population, including asymptomatic cases, is estimated to be 0.5%. Some patients develop severe symptoms, including seizures and focal neurological deficits, whereas others remain asymptomatic. The causes of this remarkable presentation heterogeneity within a primarily monogenic disease remain poorly understood. METHODS: We established a chronic mouse model of cerebral cavernous malformations, induced by postnatal ablation of Krit1 with Pdgfb-CreERT2, and examined lesion progression in these mice with T2-weighted 7T magnetic resonance imaging (MRI). We also established a modified protocol for dynamic contrast-enhanced MRI and produced quantitative maps of gadolinium tracer gadobenate dimeglumine. After terminal imaging, brain slices were stained with antibodies against microglia, astrocytes, and endothelial cells. RESULTS: These mice develop cerebral cavernous malformations lesions gradually over 4 to 5 months of age throughout the brain. Precise volumetric analysis of individual lesions revealed nonmonotonous behavior, with some lesions temporarily growing smaller. However, the cumulative lesional volume invariably increased over time and after about 2 months followed a power trend. Using dynamic contrast-enhanced MRI, we produced quantitative maps of gadolinium in the lesions, indicating a high degree of heterogeneity in lesional permeability. MRI properties of the lesions were correlated with cellular markers for endothelial cells, astrocytes, and microglia. Multivariate comparisons of MRI properties of the lesions with cellular markers for endothelial and glial cells revealed that increased cell density surrounding lesions correlates with stability, whereas denser vasculature within and surrounding the lesions may correlate with high permeability. CONCLUSIONS: Our results lay a foundation for better understanding individual lesion properties and provide a comprehensive preclinical platform for testing new drug and gene therapies for controlling cerebral cavernous malformations.

Microglial Calcium Waves During the Hyperacute Phase of Ischemic Stroke.

BACKGROUND AND PURPOSE: Ischemic injury triggers multiple pathological responses in the brain tissue, including spreading depolarizations across the cerebral cortex (cortical spreading depolarizations [CSD]). Microglia have been recently shown to play a significant role in the propagation of CSD. However, the intracellular responses of myeloid cells during ischemic stroke have not been investigated. METHODS: We have studied intracellular calcium activity in cortical microglia in the stroke model of the middle cerebral artery occlusion, using the murine Polr2a-based and Cre-dependent GCaMP5 and tdTomato reporter (PC::G5-tdT). High-speed 2-photon microscopy through cranial windows was employed to record signals from genetically encoded indicators of calcium. Inflammatory stimuli and pharmacological inhibition were used to modulate microglial calcium responses in the somatosensory cortex. RESULTS: In vivo imaging revealed periodical calcium activity in microglia during the hyperacute phase of ischemic stroke. This activity was more frequent during the first 6 hours after occlusion, but the amplitudes of calcium transients became larger at later time points. Consistent with CSD nature of these events, we reproducibly triggered comparable calcium transients with microinjections of potassium chloride (KCl) into adjacent cortical areas. Furthermore, lipopolysaccharide-induced peripheral inflammation, mimicking sterile inflammation during ischemic stroke, produced significantly greater microglial calcium transients during CSD. Finally, in vivo pharmacological analysis with CRAC (calcium release-activated channel) inhibitor CM-EX-137 demonstrated that CSD-associated microglial calcium transients after KCl microinjections are mediated at least in part by the CRAC mechanism. CONCLUSIONS: Our findings demonstrate that microglia participate in ischemic brain injury via previously undetected mechanisms, which may provide new avenues for therapeutic interventions.

Arteriovenous malformation presenting with epilepsy: a multimodal approach to diagnosis and treatment.

Arteriovenous malformation (AVM) presenting with epilepsy significantly impacts patient quality of life, and it should be considered very much a seizure disorder. Although hemorrhage prevention is the primary treatment aim of AVM surgery, seizure control should also be at the forefront of therapeutic management. Several hemodynamic and morphological characteristics of AVM have been identified to be associated with seizure presentation. This includes increased AVM flow, presence of long pial draining vein, venous outflow obstruction, and frontotemporal location, among other aspects. With the advent of high-throughput image processing and quantification methods, new radiographic attributes of AVM-related epilepsy have been identified. With respect to therapy, several treatment approaches are available, including conservative management or interventional modalities; this includes microsurgery, radiosurgery, and embolization or a combination thereof. Many studies, especially in the domain of microsurgery and radiosurgery, evaluate both techniques with respect to seizure outcomes. The advantage of microsurgery lies in superior AVM obliteration rates and swift seizure response. In addition, by incorporating electrophysiological monitoring during AVM resection, adjacent or even remote epileptogenic foci can be identified, leading to extended lesionectomy and improved seizure control. Radiosurgery, despite resulting in reduced AVM obliteration and prolonged time to seizure freedom, avoids the risks of surgery altogether and may provide seizure control through various antiepileptic mechanisms. Embolization continues to be used as an adjuvant for both microsurgery and radiosurgery. In this study, the authors review the latest imaging techniques in characterizing AVM-related epilepsy, in addition to reviewing each treatment modality.

Endoscopic endonasal surgery outcomes for pediatric craniopharyngioma: a systematic review.

OBJECTIVE: The goal of this study was to systematically review the outcomes of endoscopic endonasal surgery (EES) for pediatric craniopharyngiomas so as to assess its safety and efficacy. METHODS: A systematic literature review was performed using the PubMed and MEDLINE databases for studies published between 1986 and 2019. All studies assessing outcomes following EES for pediatric craniopharyngiomas were included. RESULTS: Of the total 48 articles identified in the original literature search, 13 studies were ultimately selected. This includes comparative studies with other surgical approaches, retrospective cohort studies, and case series. CONCLUSIONS: EES for pediatric craniopharyngiomas is a safe and efficacious alternative to other surgical approaches. Achieving gross-total resection with minimal complications is feasible with EES and is comparable, if not superior in some cases, to traditional means of resection. Ideally, a randomized controlled trial might be implemented in the future to further elucidate the effectiveness of EES for resection of craniopharyngiomas.

Outcomes of Surgery for Brainstem Cavernous Malformations: A Systematic Review.

Background and Purpose- The goal of this study was to systematically review the outcomes and complications after surgical resection of brain stem cavernous malformations (BCMs). Methods- A systematic literature review was performed using the PubMed database for studies published between 1986 and 2018. All studies comprising ≥2 patients with surgically resected BCMs and available follow-up data were included. Data extracted from studies included patient demographics, BCM location, and surgical outcomes. Results- Eighty-six studies comprising 2493 patients (adult and pediatric) were included for final analysis. Complete resection was achieved in 92.3% (fixed-effects pooled estimate [FE], 92.9% [91.7%-94.0%]; random-effects pooled estimate [RE], 89.4% [86.5%-92.0%]) of patients, and rehemorrhage of residual BCMs occurred in 58.6% (FE, 58.8% [49.7%-67.6%]; RE, 57.2% [43.5%-70.2%]). Postoperative morbidity occurred in 34.8% (FE, 30.9% [29.0%-32.8%]; RE, 31.1% [25.8%-36.6%]) of patients. Postoperative morbidities included motor deficit in 11.0% (FE, 9.9% [8.1%-11.7%]; RE, 11.1% [7.0%-16.0%]), sensory deficit in 6.7% (FE, 6.3% [4.8%-7.9%]; RE, 7.6% [4.5%-11.5%]), tracheostomy/gastrostomy in 6.0% (FE, 5.2% [4.3%-6.1%]; RE, 3.8% [2.6%-5.3%]), and other cranial nerve deficits in 29.4% (FE, 27.6% [25.3%-29.9%]; RE, 33.9% [25.7%-42.6%]) of patients. At final follow-up, 57.9% (FE, 57.6% [55.6%-59.6%]; RE, 57.2% [52.1%-62.3%]) and 25.9% (FE, 24.1% [22.4%-25.9%]; RE, 18.5% [14.6%-22.8%]) of patients had improvement and stability of preoperative symptoms, respectively. Mortality rate was 1.6% (FE, 1.9% [1.4%-2.5%]; RE, 1.8% [1.4%-2.5%]). Conclusions- High cure rates and low rates of postoperative morbidity can be achieved with surgery in patients with BCMs. Most patients had improved preoperative symptoms at final follow-up. To avoid rehemorrhage, complete resection should be the goal of surgery.

Enhanced recovery after surgery in intramedullary and extramedullary spinal cord lesions: perioperative considerations and recommendations.

Enhanced recovery after surgery (ERAS) is an evidence-based approach developed to ameliorate the patient recovery process following surgical procedures. Employing a multimodal, multidisciplinary approach, ERAS implements strategies and treatment paradigms that have been shown to improve patient outcomes, reduce hospital length of stay, and ultimately reduce healthcare costs. With a substantial body of the literature supporting the implementation of ERAS in other surgical specialties, ERAS has only recently made its foray into spine surgery. Despite this, current studies are limited to spinal deformity and degenerative disease, with limited data regarding spinal cord surgery. This is due in part to the complex nature and rarity of spinal cord lesions, making the establishment of a formal ERAS protocol difficult. In developing an ERAS protocol, there must be a consensus on what factors are important to consider and implement. To address this, we reviewed the most recent advances in intramedullary and extramedullary spinal cord surgery in order to identify elements that influence patient outcomes. Using this information, the authors provide evidence-based recommendations with the intent of introducing a framework for future ERAS protocols with respect to treating spinal cord lesions.

Left temporal craniotomy and direct microcatheterization of the middle meningeal artery for treatment of a complex temporal dural arteriovenous fistula.

The preferred method for treating complex dural arteriovenous fistulae of the transverse and sigmoid sinuses is via endovascular, transarterial embolization using liquid embolysate. However, this treatment approach mandates access to distal dural feeding arteries that can be technically challenging by standard endovascular approaches. This video describes a left temporal craniotomy for direct stick microcatheterization of an endovascularly inaccessible distal posterior division of the middle meningeal artery for embolization of a complex left temporal dural arteriovenous fistula. The case was performed in the hybrid operative suite with biplane intraoperative angiography. Technical considerations, operative nuances, and outcomes are reviewed.The video can be found here: https://youtu.be/Dnd4yHgaKcQ.

The role of contrast-enhanced ultrasound in neurosurgical disease.

Contrast-enhanced ultrasound (CEUS) is a relatively new imaging modality in the realm of neurosurgical disease. CEUS permits the examination of blood flow through arteries, veins, and capillaries via intravascular contrast agents and allows vascular architectural mapping with extreme sensitivity and specificity. While it has established utility in other organ systems such as the liver and kidneys, CEUS has not been studied extensively in the brain. This report presents a review of the literature on the neurosurgical applications of CEUS and provides an outline of the imaging modality's role in the diagnosis, evaluation, and treatment of neurosurgical disease.

Enhanced recovery after spine surgery: a systematic review.

OBJECTIVEEnhanced recovery after surgery (ERAS) is a multidimensional approach to improving the care of surgical patients using subspecialty- and procedure-specific evidence-based protocols. The literature provides evidence of the benefits of ERAS implementation, which include expedited functional recovery, decreased postoperative morbidity, reduced costs, and improved subjective patient experience. Although extensively examined in other surgical areas, ERAS principles have been applied to spine surgery only in recent years. The authors examine studies investigating the application of ERAS programs to patients undergoing spine surgery.METHODSThe authors conducted a systematic review of the PubMed and MEDLINE databases up to November 20, 2018.RESULTSTwenty full-text articles were included in the qualitative analysis. The majority of studies were retrospective reviews of nonrandomized data sets or qualitative investigations lacking formal control groups; there was 1 protocol for a future randomized controlled trial. Most studies demonstrated reduced lengths of stay and no increase in rates of readmissions or complications after introduction of an ERAS pathway.CONCLUSIONSThese introductory studies demonstrate the potential of ERAS protocols, when applied to spine procedures, to reduce lengths of stay, accelerate return of function, minimize postoperative pain, and save costs.

Extracranial-intracranial bypass approach to cerebral revascularization: a historical perspective.

While the majority of cerebral revascularization advancements were made in the last century, it is worth noting the humble beginnings of vascular surgery throughout history to appreciate its progression and application to neurovascular pathology in the modern era. Nearly 5000 years of basic human inquiry into the vasculature and its role in neurological disease has resulted in the complex neurosurgical procedures used today to save and improve lives. This paper explores the story of the extracranial-intracranial approach to cerebral revascularization.

Clinical utility of arterial spin labeling imaging in disorders of the nervous system.

Neuroimaging is an indispensable tool in the workup and management of patients with neurological disorders. Arterial spin labeling (ASL) is an imaging modality that permits the examination of blood flow and perfusion without the need for contrast injection. Noninvasive in nature, ASL provides a feasible alternative to existing vascular imaging techniques, including angiography and perfusion imaging. While promising, ASL has yet to be fully incorporated into the diagnosis and management of neurological disorders. This article presents a review of the most recent literature on ASL, with a special focus on its use in moyamoya disease, brain neoplasms, seizures, and migraines and a commentary on recent advances in ASL that make the imaging technique more attractive as a clinically useful tool.

The biophysical role of hemodynamics in the pathogenesis of cerebral aneurysm formation and rupture.

The pathogenesis of intracranial aneurysms remains complex and multifactorial. While vascular, genetic, and epidemiological factors play a role, nascent aneurysm formation is believed to be induced by hemodynamic forces. Hemodynamic stresses and vascular insults lead to additional aneurysm and vessel remodeling. Advanced imaging techniques allow us to better define the roles of aneurysm and vessel morphology and hemodynamic parameters, such as wall shear stress, oscillatory shear index, and patterns of flow on aneurysm formation, growth, and rupture. While a complete understanding of the interplay between these hemodynamic variables remains elusive, the authors review the efforts that have been made over the past several decades in an attempt to elucidate the physical and biological interactions that govern aneurysm pathophysiology. Furthermore, the current clinical utility of hemodynamics in predicting aneurysm rupture is discussed.

Deletion of 6p25.3 Is Associated with Cerebrovascular Dolichoectasia: Report of 2 Cases.

Developmental dolichoectasia of the intracranial vessels is a rare occurrence. The authors report 2 sibling pediatric patients who were born with 6p25.3 deletion, associated with carotid and vertebrobasilar dolichoectasia. MRI imaging of both children showed asymptomatic elongation and dilation of the vertebrobasilar system and "kissing" carotid arteries. A microarray analysis was also performed for both patients, which identified a 1.5-Mb deletion of 6p25.3 covering 15 genes including FOXC1, which has been implicated in defects in vascular morphogenesis.

Intracranial Arterial Compression of the Anterior Visual Pathway.

Compression of anterior visual pathway (AVP) structures by intracranial arteries is observed not infrequently on neuroimaging. Whether or not such compression results in damage to these structures, however, remains unclear. This information is important to define as AVP compression by intracranial arteries may be a causative factor in patients with otherwise unexplained visual dysfunction. In a single centre, 37 patients with evidence of intracranial artery AVP compression demonstrated on magnetic resonance imaging were identified by retrospective review of case records over the period 2011-2017. Variables were collected, including patient demographics, visual acuity, visual fields, pupillary reactions and optic disc appearance for patients in the case series. Visual field deficits correlated with compression sites in the 37 patients examined. Internal carotid artery-optic nerve compression was the most frequent (unilateral compression n = 9, bilateral compression n = 14), followed by chiasmal compression by the anterior cerebral artery (n = 8) and a combination of optic nerve and chiasmal compression (n = 5). Visual acuity and visual fields were stable on follow-up (mean 4 years) in 24 of 26 cases (93%). We conclude that AVP compression by intracranial arteries may be a causative factor in unexplained visual dysfunction. The visual defects are largely non-progressive.

Preoperative embolization of skull base meningiomas: current indications, techniques, and pearls for complication avoidance.

Skull base meningiomas are technically challenging tumors to treat because of their deep vascular supply that can preclude early devascularization during resection. Preoperative embolization of these arterial feeders is thought to decrease blood loss and facilitate resection; however, given the complex and varied anatomy of these skull base lesions, preoperative embolization is not without risk. It is essential for both endovascular and skull base neurosurgeons to understand these risks in light of the potential benefits. The authors review the vascular anatomy of skull base meningiomas, indications for preoperative devascularization, endovascular techniques, and published results regarding embolization of these lesions.

Magnetic resonance-guided, high-intensity focused ultrasound sonolysis: potential applications for stroke.

Stroke is one of the leading causes of death worldwide and a significant source of long-term morbidity. Unfortunately, a substantial number of stroke patients either are ineligible or do not significantly benefit from contemporary medical and interventional therapies. To address this void, investigators recently made technological advances to render transcranial MR-guided, high-intensity focused ultrasound (MRg-HIFU) sonolysis a potential therapeutic option for both acute ischemic stroke (AIS)-as an alternative for patients with emergent large-vessel occlusion (ELVO) who are ineligible for endovascular mechanical thrombectomy (EMT) or as salvage therapy for patients in whom EMT fails-and intracerebral hemorrhage (ICH)-as a neoadjuvant means of clot lysis prior to surgical evacuation. Herein, the authors review the technological principles behind MRg-HIFU sonolysis, its results in in vitro and in vivo stroke models, and its potential clinical applications. As a noninvasive transcranial technique that affords rapid clot lysis, MRg-HIFU thrombolysis may develop into a therapeutic option for patients with AIS or ICH. However, additional studies of transcranial MRg-HIFU are necessary to ascertain the merit of this treatment approach for thrombolysis in both AIS and ICH, as well as its technical limitations and risks.

Dynamic assessment of venous anatomy and function in neurosurgery with real-time intraoperative multimodal ultrasound: technical note.

The relevance of the cerebral venous system is often underestimated during neurosurgical procedures. Damage to this draining system can have catastrophic implications for the patient. Surgical decision-making and planning must consider each component of the venous compartment, from the medullary draining vein to the dural sinuses and extracranial veins. Intraoperative ultrasound (ioUS) permits the real-time study of venous compartments using different modalities, thus allowing complete characterization of their anatomical and functional features. The B-mode (brightness mode) offers a high-resolution anatomical representation of veins and their relationships with lesions. Doppler modalities (color, power, spectral) allow the study of blood flow and identification of vessels to distinguish their functional characteristics. Contrast-enhanced US allows one to perform real-time angiosonography showing both the functional and the anatomical aspects of vessels. In this technical report, the authors demonstrate the different applications of multimodal ioUS in neurosurgery for identifying the anatomical and functional characteristics of the venous compartment. They discuss the general principles and technical nuances of ioUS and analyze their potential implications for the study of various venous districts during neurosurgical procedures.

Novel use of flow diversion for the treatment of aneurysms associated with arteriovenous malformations.

The use of flow-diverting stents for intracranial aneurysms has become more prevalent, and flow diverters are now routinely used beyond their initial scope of approval at the proximal internal carotid artery. Although flow diversion for the treatment of cerebral aneurysms is becoming more commonplace, there have been no reports of its use to treat flow-related cerebral aneurysms associated with arteriovenous malformations (AVMs). The authors report the cases of 2 patients whose AVM-associated aneurysms were managed with flow diversion. A 40-year-old woman presented with a history of headaches that led to the identification of an unruptured Spetzler-Martin Grade V, right parietooccipital AVM associated with 3 aneurysms of the ipsilateral internal carotid artery. Initial attempts at balloon-assisted coil embolization of the aneurysms were unsuccessful. The patient underwent placement of a flow-diverting stent across the diseased vessel; a 6-month follow-up angiogram demonstrated complete occlusion of the aneurysms. In the second case, a 57-year-old man presented with new-onset seizures, and an unruptured Spetzler-Martin Grade V, right frontal AVM associated with an irregular, wide-necked anterior communicating artery aneurysm was identified. The patient underwent placement of a flow-diverting stent, and complete occlusion of the aneurysm was observed on a 7-month follow-up angiogram. These 2 cases illustrate the potential for use of flow diversion as a treatment strategy for feeding artery aneurysms associated with AVMs. Because of the need for dual antiplatelet medications after flow diversion in this patient population, however, this strategy should be used judiciously.

Advanced imaging in acute ischemic stroke.

The evaluation and management of acute ischemic stroke has primarily relied on the use of conventional CT and MRI techniques as well as lumen imaging sequences such as CT angiography (CTA) and MR angiography (MRA). Several newer or less-established imaging modalities, including vessel wall MRI, transcranial Doppler ultrasonography, and 4D CTA and MRA, are being developed to complement conventional CT and MRI techniques. Vessel wall MRI provides high-resolution analysis of both extracranial and intracranial vasculature to help identify previously occult lesions or characteristics of lesions that may portend a worse natural history. Transcranial Doppler ultrasonography can be used in the acute setting as a minimally invasive way of identifying large vessel occlusions or monitoring the response to stroke treatment. It can also be used to assist in the workup for cryptogenic stroke or to diagnose a patent foramen ovale. Four-dimensional CTA and MRA provide a less invasive alternative to digital subtraction angiography to determine the extent of the clot burden and the degree of collateral blood flow in large vessel occlusions. Along with technological advances, these new imaging modalities are improving the diagnosis, workup, and management of acute ischemic stroke- roles that will continue to expand in the future.

Stent technology in ischemic stroke.

Atherosclerotic disease of the cerebral vasculature is a major cause of stroke worldwide. Atherosclerosis that is refractory to best medical management may require revascularization. In these instances, endovascular treatment provides a popular and safe alternative to open surgical techniques. The authors provide an overview of stent technology in the treatment of ischemic stroke, discussing the major studies evaluating stenting for extracranial carotid artery, vertebral artery, and intracranial atherosclerotic disease. The authors describe the commonly used stents with respect to their individual characteristics and technical limitations. Current and future developments in stent technology are also discussed, with areas for further innovation and clinical research.