Dural Vasculature Research Articles

Abstract 137: Management of cSDH with the Use of 10:1 Glue Hyper‐Dilution in MMA Embolization: Radiographic Follow‐up

Introduction Middle meningeal artery (MMA) embolization for the treatment of chronic subdural hematomas (cSDH) is becoming an alternative to surgical intervention. Recent literature suggests distal embolic penetration beyond visible MMA branches achieves optimal cSDH devascularization. Here, we report the mid‐term radiographic follow‐up of a hyper‐dilution glue technique for enhanced embolization of non‐visible dural vasculature. Methods A prospectively maintained IRB‐approved institutional database of the senior authors was retrospectively reviewed to identify and analyze cSDHs managed with 10:1 glue hyper‐dilution (TRUFILLTM n‐BCA liquid embolic) paradigm. Results Over a 5‐month study period (September 2022 to February 2023), 46 cases of 10:1 glue hyper‐dilution for MMA embolization were identified in 23 patients. 56% of the cases were female with an average age of 70±1.59 years. Average admission cSDH thickness was 9.3±0.8 mm with an average midline shift of 3.5±0.5 mm. Bilateral embolization was performed in 91% (n=21) of patients. Technical success was achieved in all cases without need for periprocedural rescue surgery. One postprocedural complication (2.2%), a unilateral partial facial nerve palsy (House‐Brackmann 2), was identified. All patients were discharged at their mRS baseline. Nine patients (40%) had radiographic follow‐up (mean 42±6.7 days; range 1 to 194 days). Complete resolution of the cSDH was achieved in 67% of those with follow‐up imaging (n=9) cases. In those with residual cSDH, average followup thickness was 7.2±0.8mm. Conclusion Mid‐term radiographic results of 10:1 glue hyper‐dilution for MMA embolization for enhanced non‐visible dural vasculature demonstrates a favorable safety profile compatible with the literature and encouraging resolution of cSDH. Further follow‐up and comparative studies are warranted.

Transverse Canal Foramen and Pericarotid Venous Network in Metatheria and Other Mammals

Transverse Canal Foramen and Pericarotid Venous Network in Metatheria and Other Mammals

Dural venous system: angiographic technique and correlation with ex vivo investigations

BackgroundThe dural vasculature plays a key role in several important conditions, including dural fistulas and subdural collections. While in vivo investigations of intrinsic dural arterial angioarchitecture are rare, no angiographic...

(192) The Impact of Stress and Sex on Sympathetic Regulation of Dural Vessel Tone

Migraine is a common, disruptive, and often debilitating neurological disorder that the World Health Organization classifies in the highest disability category. Migraine is up to three times more common in women than men. Attacks are commonly triggered by stress, and many migraineurs show signs of sympathetic dysregulation. While the vascular hypothesis for migraine has largely fallen from favor, there are still several lines of evidence to suggest that dysregulation of the dural vasculature may contribute to the initiation of a migraine attack. These include the evidence that migraine pain arises from dural nociceptors, that the dural vasculature is heavily innervated by both nociceptors and sympathetic post-ganglionic neurons, that vascular endothelial cells may be a source of inflammatory mediators contributing to the sensitization and activation of dural nociceptors, and that the vasculature is a primary target for CGRP, a peptide that appears to play a central role in both the initiation and maintenance of pain associated with a migraine attack. We hypothesized that stress would result in a sex-dependent loss of sympathetic control over dural vasculature. Male and female rats were randomized to one of three groups: naive, acute stress (studied right after stress) or recovery (studied 24 hrs after stress). Stress consisted of a 30-minute immobilization restraint. A bipolar electrode was placed in the superior cervical ganglion (SCG) and the skull was thinned over the middle meningeal artery. FITC-dextran was used to visualize dural blood vessels while the SCG was stimulated at differing frequencies. Vasopressin and nitroprusside were used to establish the minimum and maximum vessel diameters, respectively, per rat. Preliminary results suggest that the SCG stimulation frequency range of vessel regulation is sex-dependent and may be shifted in stressed animals. A stress-induced loss of sympathetic regulation of dural vessels could contribute to migraine initiation.

Neurogenic inflammation and its role in migraine.

The etiology of migraine pain involves sensitized meningeal afferents that densely innervate the dural vasculature. These afferents, with their cell bodies located in the trigeminal ganglion, project to the nucleus caudalis, which in turn transmits signals to higher brain centers. Factors such as chronic stress, diet, hormonal fluctuations, or events like cortical spreading depression can generate a state of "sterile inflammation" in the intracranial meninges resulting in the sensitization and activation of trigeminal meningeal nociceptors. This sterile inflammatory phenotype also referred to as neurogenic inflammation is characterized by the release of neuropeptides (such as substance P, calcitonin gene related peptide) from the trigeminal innervation. This release leads to vasodilation, plasma extravasation secondary to capillary leakage, edema, and mast cell degranulation. Although neurogenic inflammation has been observed and extensively studied in peripheral tissues, its role has been primarily investigated in the genesis and maintenance of migraine pain. While some aspects of neurogenic inflammation has been disregarded in the occurrence of migraine pain, targeted analysis of factors have opened up the possibilities of a dialogue between the neurons and immune cells in driving such a sterile neuroinflammatory state in migraine pathophysiology.

Abstract 3860: Magnetization transfer and T2-weighted MRI studies are useful for visualizing phenotypic presentations of orthotopic, patient-derived xenograft mouse models of glioblastoma

Abstract Introduction: Patient-derived xenograft (PDX) models for glioblastoma (GBM) from resected tumor tissues replicate several features of the original tumor. They are considered to be representative models to study tumor progression, and to test responses to putative therapies. Longitudinal noninvasive imaging can be useful in such investigations. To that end, we employed magnetic resonance imaging (MRI) to visualize and measure tumor burden in four different PDX models of GBM. Experimental procedures: Four orthotopic mouse PDX models, HF2587, HF2927, HF3077 and HF3253, developed from neurosphere cultures of four different human glioblastoma samples were used in the study. The neurosphere cells were implanted into the right striatum in immunocompromised nude mice (n=5-8 per model) and allowed to grow for 2-8 weeks, depending on their known growth rates from previous studies. They were imaged in a Varian 7T MRI system with the following weightings: T2, T1, magnetization transfer (MT), and contrast enhanced MRI (CE-MRI) with Magnevist as the contrast agent (CA). Following imaging, all the mice were sacrificed and their brains processed for hematoxylin and eosin (H&E) histology and human major histocompatibility complex (MHC) immunohistochemistry. Results: Tumor masses were visible as hyperintense regions on MT and T2-weighted images. The extent of such masses matched the H&E and MHC staining patterns. Ventricle enlargements seen on MRI in several mice were also confirmed by histology. Necrotic cores, when present, were observed on both imaging and on histopathology with good spatial correlations. Surprisingly, post-contrast T1 imaging did not enhance in the tumor mass or peritumorally, except in one mouse in which some intra-tumoral enhancement was observed. In all other instances from the four PDX models tested, enhancement was observed only when the tumor tissue or parts of it were contiguous with pial or dural vasculature. Conclusions: At 7 Tesla, MT-MRI and T2-weighted imaging, rather than CE-MRI, appear to be of better utility in visualizing these PDX models of GBM if MRI is chosen as the imaging modality. Since the parent tumors imaged at lower field strengths showed contrast enhancement, absence of a similar feature in these models needs additional studies to understand their vascular characteristics. Such properties may include low level of vascularization and/or relatively less leaky tumor vasculature. Another possible reason may be that the models tested represent the invasive features of GBM better than the vascular features, e.g. peritumoral ring enhancement, of larger clinical tumors with increased exposure to hypoxia. Citation Format: Tavarekere N. Nagaraja, Rasha Elmghirbi, Susan Irtenkauf, Laura Hasselbach, Baruch Tawil, Stephen L. Brown, Swayamprava Panda, Glauber Cabral, Tom Mikkelsen, James R. Ewing, Ana deCarvalho. Magnetization transfer and T2-weighted MRI studies are useful for visualizing phenotypic presentations of orthotopic, patient-derived xenograft mouse models of glioblastoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3860. doi:10.1158/1538-7445.AM2017-3860

Post-mortem imaging of the infant and perinatal dura mater and superior sagittal sinus using optical coherence tomography

Infants and young children are likely to present with subdural haemorrhage (SDH) if they are the victims of abusive head trauma. In these cases, the most accepted theory for the source of bleeding is the bridging veins traversing from the surface of the brain to the dura mater. However, some have suggested that SDH may result from leakage of blood from a dural vascular plexus. As post-mortem examination of the bridging veins and dura is challenging, and imaging modalities such as magnetic resonance and computed tomography do not have the resolution capabilities to image small blood vessels, we have trialled the use of intravascular and benchtop optical coherence tomography (OCT) systems for imaging from within the superior sagittal sinus (SSS) and through the dura during five infant/perinatal autopsies. Numerous vessel-like structures were identified using both OCT systems. Measurements taken with the intravascular rotational system indicate that the approximate median diameters of blood vessels entering anterior and posterior segments of the SSS were 110 μm (range 70 to 670 μm, n = 21) and 125 μm (range 70 to 740 μm, n = 23), respectively. For blood vessels close to the wall of the SSS, the median diameters for anterior and posterior segments of the SSS were 80 μm (range 40 to 170 μm, n = 25) and 90 μm (range 30 to 150 μm), respectively. Detailed characterisation of the dural vasculature is important to aid understanding of the source of SDH. High resolution 3-dimensional reconstructions of the infant dural vasculature may be possible with further development of OCT systems.

Expression of artemin and GFRα3 in an animal model of migraine: possible role in the pathogenesis of this disorder.

BackgroundNeurotrophic factors have been implicated in hyperalgesia and peripheral levels of these molecules are altered in migraine pathophysiology. Artemin, a vasculature-derived neurotrophic factor, contributes to pain modulation and trigeminal primary afferent sensitization through binding its selective receptor GFRα3. The distribution of artemin and GFRα3 in the dura mater raises an anatomy supports that they may be involved in migraine. In this study we evaluated the expression of artemin and GFRα3 in an animal migraine model that may be relevant for migraine.MethodsIn this study, using a rat migraine model by administration of nitroglycerin (NTG), we investigated the expression of artemin in the dura mater and GFRα3 in the trigeminal ganglia (TG) by means of quantitative reverse transcription-polymerase chain reaction, western blot and immunofluorescence labeling.ResultsArtemin immunoreactivity was found in the smooth muscle cells of dural vasculature and GFRα3 was present in cytoplasm of TG neurons. The mRNA levels of artemin and GFRα3 were significantly elevated after NTG treatment at 2 and 4 h respectively (P < 0.05). The expression of artemin protein was increased at 4 h and continually up to 8 h in the dura mater following NTG administration (P < 0.05). The expression of GFRα3 protein was elevated at 4 h and continually up to 10 h in the TG following NTG administration (P < 0.05).ConclusionThe findings suggest that artemin and GFRα3 play an important role in the pathogenesis of migraine and may represent potential therapeutic targets for the treatment of migraine.

Monosodium glutamate alters the response properties of rat trigeminovascular neurons through activation of peripheral NMDA receptors

Ingestion of monosodium glutamate (MSG) has been shown to cause headaches in healthy individuals and trigger migraine-like headaches in migraine sufferers. We combined immunohistochemistry, in vivo electrophysiology, and laser Doppler recordings of dural vasculature to investigate the effect of systemic administration of MSG on the trigeminovascular pathway. Immunohistochemical analysis confirmed the expression of NMDA receptors on nerve fibers innervating dural blood vessels and excitatory amino acid transporter 2 on dural blood vessels. Systemic administration of MSG (50mg/kg) evoked an increase in ongoing discharge in 5/6 spinal trigeminal subnucleus caudalis (SpVc) neurons with dural input recorded from male and female rats, respectively, as well as lowering their mechanical activation threshold. There were no sex-related differences in these effects of MSG. Neuronal discharge and mechanical sensitization were significantly attenuated by co-injection with the peripherally restricted NMDA receptor antagonist (2R)-amino-5-phosphonovaleric acid (APV) in both sexes. Systemic administration of MSG induced a 24.5% and 20.6% increase in dural flux in male and female rats, respectively. These results suggest that MSG-induced headache is mediated by the activation of peripheral NMDA receptors and subsequent dural vasodilation. Peripheral NMDA receptors are a potential target for the development of new drugs to treat headaches.

Effects of Voluntary Locomotion and Calcitonin Gene-Related Peptide on the Dynamics of Single Dural Vessels in Awake Mice.

The dura mater is a vascularized membrane surrounding the brain and is heavily innervated by sensory nerves. Our knowledge of the dural vasculature has been limited to pathological conditions, such as headaches, but little is known about the dural blood flow regulation during behavior. To better understand the dynamics of dural vessels during behavior, we used two-photon laser scanning microscopy (2PLSM) to measure the diameter changes of single dural and pial vessels in the awake mouse during voluntary locomotion. Surprisingly, we found that voluntary locomotion drove the constriction of dural vessels, and the dynamics of these constrictions could be captured with a linear convolution model. Dural vessel constrictions did not mirror the large increases in intracranial pressure (ICP) during locomotion, indicating that dural vessel constriction was not caused passively by compression. To study how behaviorally driven dynamics of dural vessels might be altered in pathological states, we injected the vasodilator calcitonin gene-related peptide (CGRP), which induces headache in humans. CGRP dilated dural, but not pial, vessels and significantly reduced spontaneous locomotion but did not block locomotion-induced constrictions in dural vessels. Sumatriptan, a drug commonly used to treat headaches, blocked the vascular and behavioral the effects of CGRP. These findings suggest that, in the awake animal, the diameters of dural vessels are regulated dynamically during behavior and during drug-induced pathological states.

EHMTI-0219. Quantitative histological examinations of inter- and intraindividual differences in the dural vasculature of the mouse

To examine both migraine and pulmonary hypertension (PH) we developed a hypoxic mouse model. Under hypoxic conditions (four weeks at 10% O2) mice develop typical symptoms of PH, characterized by an increased muscularization of arterial blood vessels in the lung. The vessel remodeling can be prevented by the chronic application of 5-HT2B receptor antagonists. We found that hypoxic mice also develop increased sensitivity towards the 5-HT2 receptor agonist meta-Chlorophenylpiperazine (mCPP). In contrast to the control group (normoxic mice kept at 20% O2) at low doses of 1 µg / kg body weight, mCPP triggers plasma protein extravasation (PPE) in the dura mater in hypoxic mice. Dural PPE is a quantifiable indicator of migraine-like events in animal models.

The increased distensibility of the wall of cerebral arterial network may play a role in the pathogenic mechanism of migraine headache

The aim was to evaluate whether patients with episodic migraine with (MA+) and without aura (MA-), during the interictal period of migraine would have an altered distensibility of the wall of cerebral arterial network and whether it would play a role in migraine headache. To evaluate the distensibility of the wall of cerebral arterial network, we measured the time-delay in milliseconds (ms) between the R-wave of an electrocardiogram and the arterial pulse wave of cerebral microcirculation (R-APWCMtd) on the frontal cortex detected by near-infrared spectroscopy (NIRS) in 10 patients with MA+ (age 39.5 ± 12.2 years), in 10 with MA- (age 40.3 ± 10.2 years), according to ICHD-3 criteria 2012, during the interictal period of migraine, and in 15 age-, sex- and height-matched healthy control subjects. The patients with migraine had a significantly longer R-APWCMtd than the control subjects F = 13.4, p < 0.001: MA+:+38.3 ms; MA-:+34.7 ms indicating an increased distensibility of the wall of cerebral arterial network. In multiple regression analysis, R-APWCMtd was significantly associated with migraine (R (2) = 0.50, p < 0.0001) but not with age, gender, height, migraine attack frequency and disease duration. The increased distensibility leads to an increased flow pulsatility into intracranial dural meningeal vessels that may lead to a mechanical stimulation of the nociceptors that innervate the dural vasculature. This condition may play a role in promoting the sensitization of trigeminovascular afferents and sterile inflammation within the dura mater that are fundamental to the pathogenesis of migraine headache.

Pearls and pitfalls in experimental in vivo models of migraine: Dural trigeminovascular nociception

Migraine is a disorder of the brain and is thought to involve activation of the trigeminovascular system, which includes the peripheral afferent projection to the nociceptive specific dura mater, as well as the central afferent projection to the trigeminal nucleus caudalis. Stimulation of the blood vessels of the dura mater produces pain in patients that is referred to the head similar to headache. HEADACHE MECHANISMS: The likely reason for the pain is because the vascular structures of the dura mater, including the superior sagittal sinus and middle meningeal artery, are richly innervated by a plexus of largely unmyelinated sensory nerve fibers from the ophthalmic division of the trigeminal ganglion. Stimulation of these nociceptive specific nerve fibers is painful and produces neuronal activation in the trigeminal nucleus caudalis. Preclinical models of headache have taken advantage of this primarily nociceptive pathway, and various animal models use dural trigeminovascular nociception to assay aspects of head pain. These assays measure responses at the level of the dural vasculature and the central trigeminal nucleus caudalis as a correlate of trigeminovascular activation thought to be involved in headache. This review will summarize the history of the development of models of dural trigeminovascular nociception, including intravital microscopy and laser Doppler flowmetry at the level of the vasculature, and electrophysiology and Fos techniques used to observe neuronal activation at the trigeminal nucleus caudalis. It will also describe some of pitfalls of these assays and developments for the future.

Pituitary Adenylate Cyclase-Activating Polypeptide (PACAP) Potently Dilates Middle Meningeal Arteries: Implications for Migraine

Migraine is a debilitating neurological disorder characterized by mild to severe headache that is often accompanied by aura and other neurological symptoms. Among proposed mechanisms, dilation of the dural vasculature especially the middle meningeal artery (MMA) has been implicated as one component underlying this disorder. Several regulatory peptides from trigeminal sensory and sphenopalatine postganglionic parasympathetic fibers innervating these vessels have been implicated in the process including pituitary adenylate cyclase-activating polypeptide (PACAP). Although PACAP has been well described as a potent dilator in many vascular beds, the effects of PACAP on the dural vasculature are unclear. In the current study, we examined the ability of PACAP to dilate MMAs that were isolated from rats and pressurized ex vivo. PACAP38 potently dilated pressurized MMAs with an EC(50) of 1 pM. The PAC1 receptor antagonist, PACAP(6-38), abolished MMA dilation caused by picomolar concentrations of PACAP. In contrast, cerebellar arteries isolated from the brain surface were ~1,000-fold less sensitive to PACAP than MMAs. Although cerebellar arteries expressed transcripts for all three PACAP receptor subtypes (PAC1, VPAC1, and VPAC2 receptors) by RT-PCR analyses, MMA demonstrated only PAC1 and VPAC2 receptor expression. Further, multiple variants of the PAC1 receptor were identified in the MMA. The expression of PAC1 receptors and the high potency of PACAP to induce MMA vasodilation are consistent with their potential roles in the etiology of migraine.

Discovery of potent, cyclic calcitonin gene‐related peptide receptor antagonists

Calcitonin gene-related peptide (CGRP), a potent dilator of cerebral and dural vasculature, is known to be elevated in plasma and cerebral spinal fluid during migraine attacks. Selective blockade of the CGRP receptor offers the promise of controlling migraine headache more effectively and without the side-effects associated with the use of triptans. Our efforts to develop a novel, peptide-based CGRP antagonist focused on the C-terminal portion of the peptide which is known to bind the receptor but lack agonist properties. Extensive SAR studies of the C-terminal CGRP (27-37) region identified a novel cyclic structure: Bz-Val-Tyr-cyclo[Cys-Thr-Asp-Val-Gly-Pro-Phe-Cys]-Phe-NH(2) (23) with a kb value of 0.126 nM against the cloned human CGRP receptor. Additional SAR studies directed at enhancement of potency and improvement of physicochemical properties yielded a series of analogs with kb values in the 0.05-0.10 nM range.

The role of the endothelium in migraine

Migraine, characterized by throbbing cephalalgia, has long been referred to as a ‘‘vascular headache’’ disorder. This stems from the putative role of the extracerebral dural and meningeal vasculature as the end organ of migraine pain, following release of inflammatory neurotransmitters from trigeminal nerve endings. Recognition of migraine as a risk factor for stroke has raised questions about the role of cerebral vessels. Associations of migraine with variant angina, Raynaud’s disorder, retinopathy, livedo reticularis and pre-eclampsia has led to speculation of systemic involvement of the vasculature, particularly the endothelium (1). Endothelial dysfunction, a precursor to atherosclerosis, is characterized by endothelial cell activation (manifested by inflammation and hypercoagulability) and vascular reactivity impairment. In the investigation of Perko et al. (2), the authors explore systemic endothelial-dependent vasodilatation in migraine patients and healthy controls. The experiments involve end-diastolic measurements of the brachial artery diameter before and after blood pressure cuff–induced hyperemia. Flow-mediated dilatation (FMD) refers to the percentage increase in diameter between the two measurements, and low values reflect impaired reactivity, a functional component of endothelial dysfunction. The authors found no differences in FMD between migraineurs and controls, nor between migraineurs with and without aura, suggesting a lack of systemic endothelial involvement. A strength of the study lies in the careful selection of the population, excluding those with hypertension, hypercholesterolemia, diabetes, abnormal body mass index (BMI) and known cardiovascular disease. Associated with vascular risk factors and predictive of vascular ischemic events, endothelial dysfunction has been referred to as ‘‘the ultimate risk of the risk factors’’ (3). Migraine, particularly with aura, has also been associated an elevated cardiovascular risk profile (4). By excluding subjects with or at risk of vascular disease, the design best allows for examination of the unconfounded migraine-endothelial function relationship. The authors go a step further by excluding those with increased carotid intima-media thickness (IMT), a structural marker of subclinical atherosclerosis. Some studies have shown a correlation between IMT and FMD (5), whereas others have not (6). If these structural and functional markers are related, exclusion of one of these markers may bias against finding differences between groups for the other. How do the findings of Perko, et al. of non-altered FMD in migraineurs fit in with the accumulating literature on this topic? As the authors summarize in their well-researched discussion, their findings concur with those of one study (7) but conflict with the results of several others (8–11). A recently published study, similarly measuring FMD and IMT in migraine, excluded persons with known risk factors for vascular disease, except for elevated BMI (12). There were no differences in FMD between migraine (with and without aura) patients and controls, except in a subgroup with transformed migraine. FMD did, however, correlate inversely with carotid IMT, which was increased in all of the migraine subgroups. This could be expected to occur if IMT was an earlier marker of disease, but wall thickening is usually found to follow rather than precede endothelial dysfunction. In light of the discrepant results from the handful of published studies, it is interesting to reflect on the findings of Napoli et al., who investigated vascular reactivity in migraine by examining both the endothelial and vascular smooth muscle cell (VSMC) components (13). They used plethysmography measurements of forearm blood flow (FBF) during brachial artery infusions of acetylcholine (Ach), an endothelium-dependent vasodilator, and nitroprusside, a vasodilator directly acting on VSMC. In addition to this they measured forearm production of NO, a reflection of endothelial activation, and cyclic guanosine monophosphate (cGMP),

Activation of PAR‐2 Elicits NO‐Dependent and CGRP‐Independent Dilation of the Dural Artery

The goal of this study was to determine the vascular effects of protease-activated receptor-2 (PAR-2) activation in the rat cranial vasculature. The role of PAR-2 in pain and inflammatory conditions has been established but the information available on its effects and receptor distribution in the trigeminal vascular axis is limited. We studied the dilatory function and expression of PAR-2 in the neuro-vascular circuit, critical in migraine pathogenesis. We also investigated the interaction of PAR-2 with calcitonin gene-related peptide (CGRP) and dural mast cells. We used an improved model of intravital microscopy on the closed cranial window in rats to study the vascular effects of PAR-2 activating peptides (PAR-2 APs; SLIGRL-NH(2), 2-Furoyl-LIGRLO-NH(2)) in the dural vasculature. Measurement of immunoreactive CGRP in skull halves and in trigeminal nucleus caudalis was done by using an enzyme-linked immunosorbent assay. We also analyzed the presence of PAR-2 in different migraine relevant tissues by quantitative real-time PCR and Western blot analysis. PAR-2 APs and trypsin induced a dose-dependent increase in dural artery diameter. The topical application of a nonspecific nitric oxide synthase (NOS) inhibitor, L-N(G)-Nitroarginine methyl ester, attenuated SLIGRL-NH(2) responses. Olcegepant, a CGRP receptor antagonist, did not a have significant effect on the SLIGRL-NH(2) responses, though exogenous CGRP responses were completely blocked. There was no significant release of CGRP from skull halves incubated with SLIGRL-NH(2) as compared with those incubated with the corresponding negative peptide. Chronic mast cell degranulation did not change the vascular effects of PAR-2 APs. mRNA and protein expression of PAR-2 were found throughout trigeminovasuclar axis. PAR-2 activation leads to vasodilation of dural arteries and these responses are partially mediated by nitric oxide. As PAR-2 is present throughout trigeminovasuclar axis, it may have a role in migraine pathogenesis, independent of CGRP and mast cell mediated mechanism.

Distribution of Artemin and GFRα3 Labeled Nerve Fibers in the Dura Mater of Rat

We examined the distribution of artemin and its receptor, glial cell line-derived neurotrophic factor family receptor alpha3 (GFRalpha3), in the dura mater of rats. Artemin, a member of the glial cell line-derived neurotrophic factor family, is a vasculature-derived growth factor shown to regulate migration of sympathetic neuroblasts and targeting of sympathetic innervation. The artemin receptor, GFRalpha3, is present in both sympathetic efferents and a subpopulation of nociceptive afferents. Recent evidence has shown that artemin may contribute to inflammatory hyperalgesia. The extent to which artemin is present in the dural vasculature and its relationship to GFRalpha3 containing fibers have yet to be investigated. We used retrograde labeling, double and triple labeling with immunohistochemistry on the dura mater and trigeminal ganglia of female Sprague-Dawley rats. Artemin-like immunoreactivity (-LI) was detected in the smooth muscle of dural vasculature. GFRalpha3-LI was present in nerve fibers that closely associated with tyrosine hydroxylase or calcitonin gene-related peptide (CGRP). CGRP-LI and transient receptor potential ion channel 1 (TRPV1)-LI were present in all GFRalpha3-positive dural afferents, which constituted 22% of the total population of dural afferents. These anatomical results support the hypothesis that artemin contributes to dural afferent activity, and possibly migraine pain, through modulation of both primary afferent and sympathetic systems.

Relative contributions of the middle meningeal artery and superficial temporal artery in revascularization surgery for moyamoya syndrome in children: the results of superselective angiography

The authors used postoperative superselective angiography to assess the relative contributions of the middle meningeal artery (MMA) and the superficial temporal artery (STA) to revascularization following surgery for moyamoya syndrome in children. Using the neurosurgical database at the Hospital for Sick Children, the authors reviewed the clinical and pre- and postoperative angiographic records obtained in patients with moyamoya syndrome undergoing superselective angiography. Patients were 16 years of age or younger and were undergoing revascularization surgery for moyamoya syndrome during the study period. Lateral internal carotid artery, external carotid artery, STA, and MMA angiograms were analyzed in the late arterial phase to assess the relative contributions of the STA and MMA to overall revascularization as determined by the external carotid artery injection. The total moyamoya surgical revascularization experience at the Hospital for Sick Children over a 12-year period (May 1996-December 2008) comprised 33 patients (20 girls and 13 boys) undergoing a total of 50 craniotomies. A decision was made in 2001 to perform superselective angiography postoperatively in patients with moyamoya syndrome. Superselective angiography was identified to have been performed postoperatively in 12 patients and 18 treated hemispheres, and it demonstrated that the MMA contributed more significantly than the STA in 11 (61%) of the 18 hemispheres. Seven patients were Asian, 3 patients had neurofibromatosis Type 1, 1 had Down syndrome, and 2 had no apparent risk factors (1 patient was Asian and had neurofibromatosis Type 1). Stroke had occurred in 58% of patients and transient ischemic attacks in 50% prior to surgery. Within the first 30 days of surgery, there were 2 episodes of stroke (11.7% per surgically treated hemisphere and 18.2% per patient). Seventy-eight percent of hemispheres surgically treated exhibited excellent revascularization (Matsushima Grade A) on follow-up angiography, and there were no strokes documented in any patients more than 1 month after surgery, in a long-term follow-up of mean 4.1 years. The contributions of the MMA to revascularization after pial synangiosis for moyamoya syndrome are significant and may frequently exceed the contribution of the STA when surgery is performed with preservation of dural vasculature and dural inversion.

IMAGE-GUIDED LATERAL SUBOCCIPITAL APPROACH

Being situated close to the transverse and sigmoid sinus, the asterion has traditionally been viewed as a landmark for surgical approaches to the posterior fossa. Cadaveric studies, however, have shown its variability in relation to underlying anatomic structures. We have used an image-guidance technology to determine the precise anatomic relationship between the asterion and the underlying transverse-sigmoid sinus transition (TST) complex in patients scheduled for posterior fossa surgery. The applicability of three-dimensional (3-D) volumetric image-rendering for presurgical anatomic identification and individualization of a surgical landmark was evaluated. One-millimeter computed tomographic slices were combined with venous computed tomographic angiography in 100 patients, allowing for 3-D volumetric image-rendering of the cranial bone and the dural vasculature at the same time. The spatial relationship between the asterion and the TST was recorded bilaterally by using opacity modulation of the bony surface. The location of both the asterion and the TST could be confirmed during surgery in all of these patients. It was possible to accurately visualize the asterion and the sinuses in a single volumetrically rendered 3-D image in more than 90% of the patients. The variability in the anatomic position of the asterion as shown in cadaveric studies was confirmed, providing an individualized landmark for the patients. In this series, the asterion was located from 2 mm medial to 7 mm lateral and from 10 mm inferior to 17 mm superior to the TST, respectively. Volumetric image-rendering allows for precise in vivo measurements of anatomic distances in 3-D space. It is also a valuable tool for assessing the validity of traditional surgical landmarks and individualizing them for surgical planning.