Sex and Genetic Background Effects on the Outcome of Experimental Intracranial Aneurysms.

BACKGROUND AND PURPOSE: Intracranial aneurysm formation and rupture risk are, in part, determined by genetic factors and sex. To examine their role, we compared 3 mouse strains commonly used in cerebrovascular studies in a model of intracranial aneurysm formation and rupture. METHODS: Intracranial aneurysms were induced in male CD1 (Crl:CD1[ICR]), male and female C57 (C57BL/6NCrl), and male 129Sv (129S2/SvPasCrl or 129S1/SvImJ) mice by stereotaxic injection of elastase at the skull base, combined with systemic deoxycorticosterone acetate-salt hypertension. Neurological deficits and mortality were recorded. Aneurysms and subarachnoid hemorrhage grades were quantified postmortem, either after spontaneous mortality or at 7 to 21 days if the animals survived. In separate cohorts, we examined proinflammatory mediators by quantitative reverse transcriptase-polymerase chain reaction, arterial blood pressure via the femoral artery, and the circle of Willis by intravascular latex casting. RESULTS: We found striking differences in aneurysm formation, rupture, and postrupture survival rates among the groups. 129Sv mice showed the highest rates of aneurysm rupture (80%), followed by C57 female (36%), C57 male (27%), and CD1 (21%). The risk of aneurysm rupture and the presence of unruptured aneurysms significantly differed among all 3 strains, as well as between male and female C57. The same hierarchy was observed upon Kaplan-Meier analysis of both overall survival and deficit-free survival. Subarachnoid hemorrhage grades were also more severe in 129Sv. CD1 mice showed the highest resistance to aneurysm rupture and the mildest outcomes. Higher mean blood pressures and the major phenotypic difference in the circle of Willis anatomy in 129Sv provided an explanation for the higher incidence of and more severe aneurysm ruptures. TNFα (tumor necrosis factor-alpha), IL-1ß (interleukin-1-beta), and CCL2 (chemokine C-C motif ligand 2) expressions did not differ among the groups. CONCLUSIONS: The outcome of elastase-induced intracranial aneurysm formation and rupture in mice depends on genetic background and shows sexual dimorphism.

Peri-Infarct Hot-Zones Have Higher Susceptibility to Optogenetic Functional Activation-Induced Spreading Depolarizations.

BACKGROUND AND PURPOSE: Spreading depolarizations (SDs) are recurrent and ostensibly spontaneous depolarization waves that may contribute to infarct progression after stroke. Somatosensory activation of the metastable peri-infarct tissue triggers peri-infarct SDs at a high rate. METHODS: We directly measured the functional activation threshold to trigger SDs in peri-infarct hot zones using optogenetic stimulation after distal middle cerebral artery occlusion in Thy1-ChR2-YFP mice. RESULTS: Optogenetic activation of peri-infarct tissue triggered SDs at a strikingly high rate (64%) compared with contralateral homotopic cortex (8%; P=0.004). Laser speckle perfusion imaging identified a residual blood flow of 31±2% of baseline marking the metastable tissue with a propensity to develop SDs. CONCLUSIONS: Our data reveal a spatially distinct increase in SD susceptibility in peri-infarct tissue where physiological levels of functional activation are capable of triggering SDs. Given the potentially deleterious effects of peri-infarct SDs, the effect of sensory overstimulation in hyperacute stroke should be examined more carefully.

Anti-migraine Calcitonin Gene-Related Peptide Receptor Antagonists Worsen Cerebral Ischemic Outcome in Mice.

OBJECTIVE: Calcitonin gene-related peptide (CGRP) pathway inhibitors are emerging treatments for migraine. CGRP-mediated vasodilation is, however, a critical rescue mechanism in ischemia. We, therefore, investigated whether gepants, small molecule CGRP receptor antagonists, worsen cerebral ischemia. METHODS: Middle cerebral artery was occluded for 12 to 60 minutes in mice. We compared infarct risk and volumes, collateral flow, and neurological deficits after pretreatment with olcegepant (single or 10 daily doses of 0.1-1mg/kg) or rimegepant (single doses of 10-100mg/kg) versus vehicle. We also determined their potency on CGRP-induced relaxations in mouse and human vessels, in vitro. RESULTS: Olcegepant (1mg/kg, single dose) increased infarct risk after 12- to 20-minute occlusions mimicking transient ischemic attacks (14/19 vs 6/18 with vehicle, relative risk = 2.21, p < 0.022), and doubled infarct volumes (p < 0.001) and worsened neurological deficits (median score = 9 vs 5 with vehicle, p = 0.008) after 60-minute occlusion. Ten daily doses of 0.1 to 1mg/kg olcegepant yielded similar results. Rimegepant 10mg/kg increased infarct volumes by 60% after 20-minute ischemia (p = 0.03); 100mg/kg caused 75% mortality after 60-minute occlusion. In familial hemiplegic migraine type 1 mice, olcegepant 1mg/kg increased infarct size after 30-minute occlusion (1.6-fold, p = 0.017). Both gepants consistently diminished collateral flow and reduced reperfusion success. Olcegepant was 10-fold more potent than rimegepant on CGRP-induced relaxations in mouse aorta. INTERPRETATION: Gepants worsened ischemic stroke in mice via collateral dysfunction. CGRP pathway blockers might thus aggravate coincidental cerebral ischemic events. The cerebrovascular safety of these agents must therefore be better delineated, especially in patients at increased risk of ischemic events or on prophylactic CGRP inhibition. ANN NEUROL 2020;88:771-784.

Non-invasively triggered spreading depolarizations induce a rapid pro-inflammatory response in cerebral cortex.

Cortical spreading depolarization (CSD) induces pro-inflammatory gene expression in brain tissue. However, previous studies assessing the relationship between CSD and inflammation have used invasive methods that directly trigger inflammation. To eliminate the injury confounder, we induced CSDs non-invasively through intact skull using optogenetics in Thy1-channelrhodopsin-2 transgenic mice. We corroborated our findings by minimally invasive KCl-induced CSDs through thinned skull. Six CSDs induced over 1 h dramatically increased cortical interleukin-1ß (IL-1ß), chemokine (C-C motif) ligand 2 (CCL2), and tumor necrosis factor-α (TNF-α) mRNA expression peaking around 1, 2 and 4 h, respectively. Interleukin-6 (IL-6) and intercellular adhesion molecule-1 (ICAM-1) were only modestly elevated. A single CSD also increased IL-1ß, CCL2, and TNF-α, and revealed an ultra-early IL-1ß response within 10 min. The response was blunted in IL-1 receptor-1 knockout mice, implicating IL-1ß as an upstream mediator, and suppressed by dexamethasone, but not ibuprofen. CSD did not alter systemic inflammatory indices. In summary, this is the first report of pro-inflammatory gene expression after non-invasively induced CSDs. Altogether, our data provide novel insights into the role of CSD-induced neuroinflammation in migraine headache pathogenesis and have implications for the inflammatory processes in acute brain injury where numerous CSDs occur for days.

Decreased wall shear stress at high-pressure areas predicts the rupture point in ruptured intracranial aneurysms.

OBJECTIVE: Degenerative cerebral aneurysm walls are associated with aneurysm rupture and subarachnoid hemorrhage. Thin-walled regions (TWRs) represent fragile areas that may eventually lead to aneurysm rupture. Previous computational fluid dynamics (CFD) studies reported the correlation of maximum pressure (Pmax) areas and TWRs; however, the correlation with aneurysm rupture has not been established. This study aims to investigate this hemodynamic correlation. METHODS: The aneurysmal wall surface at the Pmax areas was intraoperatively evaluated using a fluid flow formula under pulsatile blood flow conditions in 23 patients with 23 saccular middle cerebral artery (MCA) bifurcation aneurysms (16 unruptured and 7 ruptured). The pressure difference (Pd) at the Pmax areas was calculated by subtracting the average pressure (Pave) from the Pmax and normalized by dividing this by the dynamic pressure at the aneurysm inlet side. The wall shear stress (WSS) was also calculated at the Pmax areas, aneurysm dome, and parent artery. These hemodynamic parameters were used to validate the correlation with TWRs in unruptured MCA aneurysms. The characteristic hemodynamic parameters at the rupture points in ruptured MCA aneurysms were then determined. RESULTS: In 13 of 16 unruptured aneurysms (81.2%), Pmax areas were identified that corresponded to TWRs. In 5 of the 7 ruptured cerebral aneurysms, the Pmax areas coincided with the rupture point. At these areas, the Pd values were not higher than those of the TWRs in unruptured cerebral aneurysms; however, minimum WSS, time-averaged WSS, and normalized WSS at the rupture point were significantly lower than those of the TWRs in unruptured aneurysms (p < 0.01). CONCLUSIONS: At the Pmax area of TWRs, decreased WSS appears to be the crucial hemodynamic parameter that indicates the risk of aneurysm rupture.

Posterior Inferior Cerebellar Artery Thrombosed Aneurysm Associated with Persistent Primitive Hypoglossal Artery Successfully Treated with Condylar Fossa Approach.

A 68-year-old woman presented with generalized seizure due to the left internal carotid artery (ICA) aneurysmal compression of the ipsilateral medial temporal lobe. Computed tomography angiography (CTA) revealed multiple aneurysms of the right persistent primitive hypoglossal artery (PPHA), the right ICA, and the right anterior cerebral artery (ACA). The right PPHA originated from the ICA at the level of the C1 and C2 vertebral bodies and passed through the hypoglossal canal (HC). The PPHA aneurysm was large and thrombosed, which was located at the bifurcation of the right PPHA and the right posterior inferior cerebellar artery (PICA), projecting medially to compress the medulla oblongata. Since this patient had no neurological deficits, sequential imaging studies were performed to follow this lesion, which showed gradual growth of the PPHA aneurysm with further compression of the brain stem. Although the patient remained neurologically intact, considering the growing tendency clipping of the aneurysm was performed. Drilling of the condylar fossa was necessary to expose the proximal portion of the PPHA inside the HC. The key of this surgery was the preoperative imaging studies to fully understand the anatomical structures. The PPHA was fully exposed from the dura to the corner its turning inferiorly without damaging the occipital condylar facet. Utilizing this technique, the neck ligation of the aneurysm was safely achieved without any surgical complications.

Surgical Microanatomy of the Posterior Condylar Emissary Vein and its Anatomical Variations for the Transcondylar Fossa Approach.

BACKGROUND: It is essential to identify and be aware of the anatomy of the posterior condylar emissary vein (PCEV) for achieving an adequate operative field for the transcondylar fossa approach (TCFA). OBJECTIVE: To describe the variations in the drainage patterns of PCEVs and the technical issues encountered in such cases. METHODS: This was a retrospective analysis of the anatomy of PCEVs in 104 sides in 52 cases treated by the TCFA. Preoperative findings of multidetector-row computed tomography (CT) and CT venography (CTV) were compared with the intraoperative findings. The drainage patterns were classified as 5 types: the sigmoid sinus (SS), jugular bulb (JB), occipital sinus (OS), anterior condylar emissary vein (ACEV), and marginal sinus (MS). RESULTS: The SS, JB, ACEV, and OS types were observed in 33 (31.7%), 42 (40.3%), 8 (7.7%), and 1 (1.0%) side(s), respectively. One side (1.0%) each had combined drainage from MS and JB, and ACEV and JB, respectively. In 17 sides (16.3%), the PCEVs and posterior condylar canals could not be identified on CT and CTV. CONCLUSIONS: Preoperative CT and CTV findings correlated well with the intraoperative findings. To make a sufficient operative field for TCFA, PCEVs should be appropriately dealt with based on the preoperative knowledge of their running course, pattern, and origin.

Bypass Revascularization Applied to the Posterior Cerebral Artery.

BACKGROUND: The application of bypass procedures to the posterior cerebral artery (PCA) in combination with proximal clipping or trapping is a useful option for the treatment of complex posterior circulation aneurysms, especially those of the PCA. Because of its course around the midbrain through various cisterns, different approaches are required to access the PCA. OBJECTIVE: The presented study analyzes a retrospective case series of bypass procedures to the PCA to investigate the relevant treatment strategies and their outcomes. METHODS: Seven patients with bypass procedures to the PCA bypass were analyzed. The location of the aneurysms, approaches, site of anastomosis, bypass patency, pre- and postoperative modified Rankin Scale scores, and transient and permanent morbidity were assessed. RESULTS: Analyzed patients were treated for intracranial aneurysm located on the P2 (n = 3) or P3 (n = 2) of the PCA, bilateral vertebral artery dissecting aneurysm (n = 1) or internal carotid artery-posterior communicating artery aneurysm (n = 1). The following approaches were used: anterior temporal approach (n = 2), anterior temporal approach combined with subtemporal approach (n = 2), combined transpetrosal approach (n = 1), posterior interhemispheric approach (n = 1), and posterior interhemispheric approach with subtemporal approach (n = 1). All bypasses were patent. Permanent morbidity occurred in 2 patients via cognitive dysfunction (n = 1) and hemiparesis (n = 1). CONCLUSIONS: Bypass revascularization of the PCA territory is effective for the treatment of complex vascular lesions affecting the posterior circulation. To address the various surgical segments of the PCA, different approaches are required. Combined approaches allow access to the PCA proximal and distal from the lesion.

Radical treatment for bilateral vertebral artery dissecting aneurysms by reconstruction of the vertebral artery.

OBJECTIVE Bilateral vertebral artery dissecting aneurysms (VADAs) have a poor prognosis because progressive enlargement of the aneurysms compresses the brainstem or causes subarachnoid hemorrhage. The trapping of 1 vertebral artery (VA) places increased hemodynamic stress on the contralateral VA and may lead to enlargement and rupture. Therefore, management strategies are controversial. This study describes a radical treatment for bilateral VADAs using bypass surgery. METHODS Seven patients with bilateral VADAs were included. Three patients were treated by trapping of 1 VA via coiling or clipping at another hospital; the previously treated VA in 1 patient and the contralateral untreated VA in 2 patients subsequently enlarged. The other 4 patients presented without previous intervention and progressive enlargement of the aneurysms. RESULTS The post-coil embolization patients underwent V3-posterior cerebral artery (PCA) bypass and trapping. The other 4 patients underwent VA reconstruction via V3-V4 or V4-V4 bypass, with contralateral trapping on a separate day in 3 patients and observation in 1 patient. Perioperative complications included 1 case of cerebrospinal fluid leakage for which the patient required an additional operation, 1 case of dysphagia and facial palsy due to sigmoid sinus thrombosis, and 1 case of dysphagia. The long-term outcomes of these patients were favorable. CONCLUSIONS Patients with bilateral VADAs require treatment on both sides. If VA trapping is performed first, the treatment options for the other side are limited to V3-PCA bypass and trapping. This procedure is effective; however, it is also invasive and technically difficult. In cases of bilateral VADAs in which it is feasible to reconstruct 1 side, the best approach is to begin by reconstructing the VA that appears technically easiest, followed by trapping of the contralateral VADA. This strategy allows enough time to suture vessels because contralateral reverse flow is maintained.

Radical resection of a craniopharyngioma via the extradural anterior temporal approach with zygomatic arch osteotomy.

BACKGROUND: Though the extradural anterior temporal approach (EDATA) with zygomatic osteotomy is useful, there are only few reports of this approach being used for craniopharyngioma resection. Herein, we report our surgical case series and the technical importance of EDATA for the radical removal of a craniopharyngioma. METHODS: We report 7 cases of craniopharyngiomas treated surgically between April 1999 and October 2015. The surgical approaches, clinical presentation, pre and postoperative radiographic examination results, surgical outcomes, and morbidity were analyzed. RESULTS: The mean follow-up period was 89.1 months. The surgical approach was EDATA with zygomatic osteotomy in 4, combined interhemispheric translamina terminalis approach (IHTLA) and trans-sylvian anterior temporal approach (ATA) in 2, and IHTLA in 1 patient. Complete tumor resection was achieved in all cases, without any recurrence during the follow-up period. Transient morbidities were oculomotor nerve palsy in 2, and meningitis and hydrocephalus in 1 patient. There was 1 case of permanent morbidity due to hydrocephalus that needed a ventriculoperitoneal shunt, and 1 case of blindness on the operative side. Visual acuity and visual field improved in 4 cases, showed no change in 2 cases, and deteriorated in 1 case. Though the pituitary stalk was preserved in 2 cases, all 7 cases needed total hormone replacement therapy. CONCLUSION: EDATA with zygomatic osteotomy ensures sufficient mobility of the internal carotid artery, and provides a good lateral and look up operative view. Hence, it can be used effectively for radical resection of craniopharyngiomas through the opticocarotid space and retrocarotid space.

Direct Microsurgical Embolectomy for an Acute Distal Basilar Artery Occlusion.

BACKGROUND: Acute basilar artery occlusion is associated with high mortality rates, up to 35%-40%. Early revascularization by intravenous thrombolysis, intra-arterial thrombolysis, and endovascular mechanical embolectomy is considered the best option to date. The objective of this technical report is to present the direct microsurgical embolectomy technique for an acute distal basilar artery occlusion as an urgent life-saving revascularization procedure. METHODS: A 71-year-old male patient suffered from an acute embolic basilar artery occlusion and became unconscious (Glasgow Coma Scale 4). Computed tomography angiography and MRA revealed the distal basilar artery occlusion along with an increased diffusion-weighted imaging signal in the corresponding territory. After an individual case discussion, the patient underwent a microsurgical embolectomy via a frontotemporal craniotomy and an anterior temporal approach. RESULTS: Intraoperative indocyanine green and postoperative computed tomography angiography revealed complete revascularization of the previously occluded basilar quadfurcation. The patient steadily recovered and was able to walk with assistance after 4 weeks. CONCLUSIONS: Microsurgical embolectomy can be an effective treatment option for acute distal basilar artery occlusion in selected cases with experienced surgeons, but a critical preoperative decision-making process is needed.

Technical Description of the Medial and Lateral Anterior Temporal Approach for the Treatment of Complex Proximal Posterior Cerebral Artery Aneurysms.

BACKGROUND: Posterior cerebral artery (PCA) aneurysms are often fusiform and associated with multiple intracranial aneurysms. A bypass procedure in combination with proximal occlusion or aneurysm trapping is considered to be effective for the treatment of patients with complex PCA aneurysms. Because of the deep, narrowed surgical corridor and the surrounding sensitive neuroanatomic structures, microsurgical procedures applied to the PCA are technically demanding. The authors present a technical report of a complex aneurysm formation located at the postcommunicating segment of the PCA (PCA-P2) treated via an anterior temporal approach. METHODS: A 68-year-old woman had an unruptured PCA-P2 aneurysm formation, which was discovered incidentally. The fusiform aneurysm shape of the distal aneurysm aggravated direct microsurgical and endovascular treatment. After an individual case discussion, the patient underwent a microsurgical clipping of the proximal P2 segment aneurysm and the distal PCA-P2 segment aneurysm was treated by trapping after the application of a superficial temporal artery (STA) to PCA-P2 bypass using an anterior temporal approach. RESULTS: Postoperative computed tomography angiography showed the exclusion of the proximal PCA-P2 aneurysm and an adequate flow from the STA to PCA-P2 bypass to the distal PCA segments. The patient showed a modified Rankin scale of 0 after follow-up at 1 and 3 months. CONCLUSIONS: The anterior temporal approach is feasible for the microsurgical management of complex postcommunicating PCA aneurysms and the application of bypass procedures.

Surgical Strategy for Complex Anterior Cerebral Artery Aneurysms: Retrospective Case Series and Literature Review.

OBJECTIVE: Giant, or complex, aneurysms of the anterior cerebral artery (ACA) are rare, but their surgical treatment is important. The authors describe their experiences with bypasses for complex ACA aneurysms and discuss the new classification of ACA bypasses, the concept of using bypasses for insurance during the approach to the aneurysm, and simplifying the surgical algorithms for these complex ACA aneurysms. METHODS: Over a 19-year period, 7 cases of complex ACA aneurysm were treated with bypasses and reviewed retrospectively. The bypasses were classified into 4 groups according to donor blood flow: internal carotid artery-ACA, external carotid artery-ACA, communicating bypass, and reconstruction bypass of the ipsilateral postcommunicating ACA. RESULTS: The cases included 1 precommunicating aneurysm, 3 communicating aneurysms, 2 postcommunicating aneurysms, and 1 double aneurysm (communicating and postcommunicating). The types of bypass included 1 internal carotid artery-ACA, 6 communicating bypasses, 3 external carotid artery-ACAs, and 2 reconstruction bypass of the postcommunicating ACA. Postoperative modified Rankin Scale scores were 0 (6 cases) and 3 (1 case of a communicating aneurysm with complicated memory disturbance because of infarction). One case revealed asymptomatic infarction. CONCLUSIONS: Surgical treatment of complex ACA aneurysms requires knowledge of a variety of bypass techniques. Although the type of bypass should be selected according to patient-specific anatomy and the neurosurgeon's preference, the new classification of bypass-specified ACA aneurysms may alter the way surgeons think about ACA bypasses, and in combination with the concept of the protective bypass, can be used to establish a comprehensive algorithm for each type of complex ACA aneurysm.

Slow progression of calcified cerebellar metastasis from ovarian cancer: a case report and review of the literature.

The report describes a rare case of a patient with a calcified cerebellar metastasis arising from a primary ovarian cancer. The patient was a 33-year-old woman with a long history of stage IIIc ovarian cancer who had undergone transabdominal hysterectomy and bilateral oophorectomy followed by chemotherapy with gemcitabine hydrochloride. Incidentally, computed tomography (CT) revealed a cerebellar tumor with calcification. The size of the tumor gradually increased, and lateral suboccipital craniotomy was performed for gross total removal of the tumor. The histological diagnosis was ovarian mucinous adenocarcinoma. The patient's postoperative course was uneventful, and she was discharged two days after surgery. Brain metastases from ovarian cancer are rare. In the review of metastatic brain tumors arising from a primary ovarian cancer in the Department of Obstetrics and Gynecology at our institution, this phenomenon was noted in only 10 cases (0.24%) of 4,158 patients with ovarian cancer seen at our center over a period of 8 years. Moreover, only three cases of calcified metastatic brain tumor have been reported previously. In conclusion, complete tumor resection may be an acceptable approach for patients with calcified metastatic tumors both for therapeutic considerations and to obtain tissue for confirmation of histopathological diagnosis. Metastatic brain tumors can be calcified, and should be considered within the differential diagnosis of calcified intracranial lesions to avoid any delay in diagnosis or treatment.

Surgical treatment of a giant liposarcoma in a Japanese man.

We report a case of a rapidly progressing giant retroperitoneal liposarcoma weighing 22 kg in a 41-year-old Japanese man, successfully treated with surgical excision. To our knowledge, this is the largest liposarcoma in the Japanese population reported in the literature.

Design, synthesis, and structure-activity relationship of new isobenzofuranone ligands of protein kinase C.

Protein kinase C (PKC) is a family of enzymes, which play important roles in intracellular signal transduction. We have designed novel PKC ligands having an isobenzofuranone template, based on the proposed interaction of DAG (1,2-diacyl-sn-glycerol) with the PKCdelta C1B ligand-binding domain. Several isobenzofuranone derivatives were synthesized and their PKCalpha binding activities were evaluated. The pivaloyl derivative 1f was found to be a strong PKCalpha ligand, and the structure-activity relationship is well explained by our proposed binding model.

Evaluation of series of isobenzofuranone dimers as PKCalpha ligands: implication for the distance between the two ligand binding sites.

Protein kinase C (PKC) is a family of enzymes, which play important roles in intracellular signal transduction. To examine the distance between the two ligand binding sites (C1A and C1B) of PKC, we designed and synthesized two series of isobenzofuranone dimers. Peak binding activities were observed for the C3-acyl chain dimers having a C10-C12 linker and for the C7 dimers having a C14-C16.