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Background: Rosette-forming glioneuronal tumors (RGNTs) are rare tumors composed of mixed glial and neurocytic components. Most lesions are confined to the posterior fossa, especially in the region of the fourth ventricle, in young adults. In few instances, diffuse involvement of the supratentorial region is identified, thereby creating significant challenges in diagnosis, surgical intervention, and prognostication., Observations: The authors present a 23-year-old female with chronic headaches, papilledema, and hydrocephalus who underwent radiographic evaluation revealing obstructive hydrocephalus and diffuse supratentorial enhancing and nonenhancing cystic and nodular lesions. The patient underwent a right frontal craniotomy and septostomy. An exophytic nonenhancing right frontal horn lesion was resected, and an enhancing third-ventricular lesion was biopsied. Final pathology of both of the lesions sampled was consistent with RGNT. Next-generation sequencing demonstrated tumor alterations in the FGFR-1 and PIK3CA genes. Targeted therapy with the FGFR inhibitor erdafitinib demonstrated a partial remission., Lessons: Diffuse supratentorial spread of RGNT is an extremely rare presentation of an already uncommon pathology. In some cases, gross-total resection may not be feasible. Goals of surgery include acquiring tissue for diagnosis, maximizing safe resection, and treating any associated hydrocephalus. FGFR inhibitors may be of benefit in cases of disease progression.

Extracranial-intracranial bypass has been shown to be effective in the surgical treatment of moyamoya disease, complex aneurysms, and tumors that involve proximal vasculature in carefully selected patients. Branches of the superficial temporal artery (STA) are used commonly for the bypass surgery; however, an appropriate length of the donor vessel must be harvested to avoid failure secondary to anastomotic tension. The goal of this cadaveric study was to investigate quantitatively operative techniques that can increase the STA length available to facilitate tension-free STA-middle cerebral artery (MCA) bypass. We conducted a cadaveric study using a total of 16 sides in eight cadavers. Measurements of the STA trunk with its frontal branch (STAfb) were taken before and after skeletonization and detethering of the STA with the STAfb and mobilization of the parietal branch of the STA. A final measurement of the STA with the STAfb was taken for the free length gained toward visible proximal cortical branches of the MCA. Paired student's t-tests were used to compare the mean length before and after mobilization and unpaired t-tests to analyze according to laterality. The mean length of the STA with the STAfb was 9.0 cm prior to modification. After skeletonization and mobilization, the mean lengths increased significantly to 10.5 and 11.3 cm, respectively (p < 0.05). Especially in the cases that had the coiled and tortuous STA, skeletonization was considerably effective to increase the length of the STA with the STAfb. After simulating a bypass by bringing the STAfb to the recipient MCA site, the mean extended length of the STA with the STAfb was 3.0 cm. There were no statistically significant differences between sides in all measurements. We report a significant increase in the mean STA length available (3.0 cm) following skeletonization and mobilization. Clinical applications of the extended length of the STA with the STAfb may facilitate tension-free STA-MCA bypasses and improve outcomes. Further studies are needed in a clinical context., (© 2021 American Association of Clinical Anatomists.)

Background: Middle fossa (MF) encephaloceles are rare lesions resulting from herniation through defects in the tegmen tympani or mastoideum. Underlying etiologies and clinical presentations are variable. Surgical goals include fistula obliteration, resection of nonfunctioning parenchyma, and dehiscence repair. The middle cranial fossa approach (MCFA), transmastoid approach (TMA), and combined (MCFA + TMA) approaches have been described. The minimally invasive TMA provides excellent exposure of the pathology and allows for ample working room to repair the defect., Objective: To present short-term follow-up results in patients treated via the TM repair at our institution., Methods: A retrospective review of patients with symptomatic encephaloceles treated via the TMA by our multidisciplinary team. Patient demographics, clinical presentations, intraoperative findings, repair technique, and outcomes were highlighted., Results: A total of 16 encephaloceles in 13 patients were treated. Defect etiologies included spontaneous (50.0%), secondary to chronic infection (25.0%), or cholesteatoma (18.8%). Defects were most often within the tegmen mastoideum (68.8%). Average length of surgery was 3.3 h (95% CI: 2.86-3.67) and length of stay 3.9 d (95% CI: 3.09-4.79). On short-term follow-up (average 11.5 mo), no patients experienced postoperative cerebrospinal fluid leak or recurrence. The majority of patients (83.3%) experienced confirmed improvement or stabilization of hearing., Conclusion: MF encephaloceles present with various clinical manifestations and result from multiple underlying etiologies. The TMA is an alternative to craniotomy and our short-term results suggest that this approach may be utilized effectively in appropriately selected cases., (© Congress of Neurological Surgeons 2021.)

Dissecting intracranial pseudoaneurysms (IPs) are associated with a high incidence of rupture and poor neurologic outcomes. Lesions in the posterior circulation are particularly malignant and pose even greater management challenges. Traditional management consists of microsurgical vessel sacrifice with or without bypass. Flow diversion (FD) in the setting of subarachnoid hemorrhage (SAH) represents a reconstructive treatment option and can be paired with coil embolization to promote more rapid thrombosis of the lesion. We report a case of a ruptured dissecting vertebral artery (VA) IP successfully acutely treated with coil-assisted FD. A 53-year-old male presented with a right V4 dissection spanning the origin of the posterior inferior cerebellar artery and associated ruptured V4 IP. The patient was treated with coil-assisted FD. Oral dual-antiplatelet therapy (DAPT) was initiated during the procedure, and intravenous tirofiban was used as a bridging agent. Immediate obliteration of the IP was achieved, with near-complete resolution of the dissection within 48 h. The patient made a complete recovery, and angiography at 6 weeks confirmed total IP obliteration, reconstruction of the VA, and a patent stent. The use of FD and DAPT in the setting of acute SAH remains controversial. We believe that coil-assisted FD in carefully selected patients offers significant advantages over traditional microsurgical and endovascular options. The risks posed by DAPT and potential for delayed thrombosis with FD can be effectively mitigated with planning and the development of protocols. We discuss the current literature in the context of our case and review the challenges associated with treating these often devastating lesions., Competing Interests: There are no conflicts of interest., (Copyright: © 2021 Brain Circulation.)

Patient selection for endovascular intervention in extracranial carotid disease is centered on vascular anatomy. We review anatomical considerations for non-traumatic disease and offer guidelines in patient selection and management. We conducted a systematic literature review without meta-analysis for studies involving anatomical considerations in extracranial carotid intervention for non-traumatic disease. Anatomical considerations discussed included aortic arch variants, degree of vessel stenosis, angulation, tortuosity, and anomalous origins, and atheromatous plaque morphology, composition, and location. Available literature suggests that anatomical risks of morbidity are largely secondary to increased procedural times and difficulties in intervention system delivery. We recommend the prioritization of endovascular techniques on an individual basis in cases where accessible systems and surgeon familiarity provide an acceptable likelihood of rapid access and device deployment., Competing Interests: The authors declare no conflict of interest.

Objective  Many external anatomical landmarks have been used for approximating deeper, intracranial structures. Herein, we evaluate the attachment of the longissimus capitis (LC) on the mastoid process as a landmark for the underlying sigmoid sinus. Methods  Adult cadavers underwent dissection of the posterior occiput with special attention to the attachment of the LC muscle. Once the periphery of the muscle's tendon of attachment was determined, a burr hole was made in this area and evaluated internally for its relationship to the sigmoid sinus. Results  From an intracranial view, burr holes on all sides were over the sigmoid sinus and just slightly lateral to the center of the sinus. The distance from the midline to the medial border of the insertion of the LC had a mean of 63.0 ± 7.2 mm. The width of the tendon of insertion of the LC on the mastoid process had a mean of 17.6 ± 5.7 mm. The length of the tendon insertion of the LC had a mean of 14.7 ± 4.7 mm. The distance from the inferior border of the insertion of the LC to the tip of the mastoid process had a mean of 6.2 ± 4.5 mm. Conclusion  To our knowledge, use of the attachment site of the LC on the mastoid process as an external landmark for the underlying sigmoid sinus has not previously been reported. Based on our cadaveric findings, the sigmoid sinus is centered under the attachment of the LC regardless of the width of its tendon., Competing Interests: Conflict of Interest None declared., (Thieme. All rights reserved.)

The prevalence of intracranial aneurysms (IAs) is higher in patients with internal carotid artery (ICA) stenosis, likely due to alterations in intracranial hemodynamics. Severe stenosis or occlusion of one ICA may result in increased demand and altered hemodynamics in the contralateral ICA, thus increasing the risk of contralateral IA formation. In this article, we discuss a relevant case and a comprehensive literature review as it pertains to the association of ICA stenosis and IA. Our patient was a 50-year-old female with a chronic asymptomatic right ICA occlusion who presented with diffuse subarachnoid hemorrhage. Emergent angiography revealed left-sided A1-A2 junction, paraclinoid, left middle cerebral artery (MCA) bifurcation, and left anterior temporal artery aneurysms. Brisk filling of the right anterior circulation through the anterior communicating artery was also identified, signifying increased demand on the left ICA circulation. Complete obliteration of all aneurysms was achieved with coil embolization and clipping. For our literature review, we searched the PubMed and EMBASE databases for case reports and case series, as well as references in previously published review articles that described patients with concurrent aneurysms and ICA stenosis. We selected articles that provided adequate information about the case presentations to compare aneurysm and patient characteristics. Our review revealed a higher number of patients with multiple aneurysms contralateral (25%) to rather than ipsilateral to (6%), the ICA stenosis. We discuss the pathogenesis and management of multiple flow-related IA in the context of the existing literature related to concurrent ICA stenosis and IA., Competing Interests: There are no conflicts of interest., (Copyright: © 2020 Brain Circulation.)

Oxidative stress and chronic inflammation in arterial walls have been implicated in intracranial aneurysm (IA) formation and rupture. Dimethyl fumarate (DMF) exhibits immunomodulatory properties, partly via activation of the nuclear factor erythroid 2-related factor 2 (Nrf2) pathway which reduces oxidative stress by inducing the antioxidant response element (ARE). This study evaluated the effects of DMF both in vitro, using tumor necrosis factor (TNF)-α-treated vascular smooth muscle cells (VSMC), and in vivo, using a murine elastase model to induce aneurysm formation. The mice were treated with either DMF at 100 mg/kg/day P.O. or vehicle for two weeks. DMF treatment protected VSMCs from TNF-α-induced inflammation as demonstrated by its downregulation of cytokines and upregulation of Nrf2 and smooth muscle cell markers. At higher doses, DMF also inhibited the pro-proliferative action of TNF-α by increasing apoptosis which protected the cells from aponecrosis. In mice, DMF treatment significantly decreased the incidence of aneurysm formation and rupture, at the same time increasing Nrf2 levels. DMF demonstrated a neuroprotective effect in mice with a resultant inhibition of oxidative stress, inflammation, and fibrosis in the cerebrovasculature. This suggests a potential role for DMF as a rescue therapy for patients at risk for formation and rupture of IAs.

Background: Cauda equina syndrome (CES) results from the dysfunction of the lumbar, sacral, and coccygeal rootlets composing the cauda equina. The underlying etiology is most commonly compression secondary to a large herniated lumbosacral disk; however, any pathology affecting the rootlets can result in the syndrome., Methods: We present a rare case of CES secondary to neoplastic polyradiculitis in a patient with acute myelogenous leukemia (AML) and review the pertinent literature. A 72-year-old male with a medical history of AML presented with 2 weeks of difficulty ambulating, followed by acute-onset low back pain radiating to the buttocks bilaterally., Results: Imaging of the lumbar spine demonstrated diffuse enhancement and thickening of the cauda equina rootlets. Lumbar puncture showed numerous blasts with monocytoid features consistent with AML, and the patient was diagnosed with polyradiculopathy of the cauda equina secondary to diffuse metastatic infiltration., Conclusions: Central nervous system involvement of leukemia is poorly understood, even though such lesions are not uncommon in advanced disease. As treatment has improved, many types of leukemia, such as AML, are believed to be curable, and patients with the disease are living longer. With improved survival, it is reasonable to suspect that such involvement by AML may become more common. Our patient is a classic presentation of CES secondary to diffuse infiltration by AML and serves as an example of this rare manifestation of hematologic malignancy., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Mechanisms governing cerebral aneurysm (CA) formation, progression, and rupture remain incompletely understood. However, understanding such mechanisms is critical to improving treatment for patients harboring CA. In vitro studies facilitate dissecting molecular mechanisms underlying vascular pathology and allow screening of therapies that can be subsequently explored in vivo. Cerebral vascular smooth muscle cells (VSMC) are an important constituent of the vessel wall, and phenotypic modulation of these cells to a pro-inflammatory, pro-matrix remodeling phenotype appears to be important in CA pathology. We have taken a reductionist approach using cultured cerebral VSMC to further explore CA biology. We describe techniques for culturing cerebral VSMC and outline experimental approaches incorporating these cells to study CA biology.

Background: Fistulas of the filum terminale are rare lesions that result from a fistulous connection between the artery and vein of the filum terminale. These lesions often present as progressive thoracic myelopathy secondary to venous hypertension that is transmitted to the coronal venous plexus of the spinal cord. Frequently, filum fistulas will be associated with lumbar stenosis and likely form as a result of chronic inflammation and compression. However, owing to the relative rarity of filum fistulas and the commonality of lumbar stenosis, the presence of a filum fistula could be overlooked or misdiagnosed., Case Description: We have presented the case of a 62-year-old man with severe lumbar stenosis who had presented with progressive thoracic myelopathy. The evaluation, including spinal angiography, identified a low-flow arteriovenous fistula within the filum terminale that was successfully treated with microsurgical obliteration. The patient tolerated the procedure well, with good functional recovery within 1 month., Conclusion: Just as was the case with our patient, these lesions demonstrate a high association with lumbar stenosis and tethered or tight cord syndrome. We reviewed the clinical presentation, imaging findings, surgical management, and possible mechanisms of development for these rarely encountered fistulas., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Background: Vestibular schwannomas (VS) are common slow-growing tumors that typically present with the insidious progression of unilateral hearing loss, tinnitus, vertigo, and gait imbalance. Clinically significant intratumoral acute hemorrhage is exceedingly rare and can present with the acute onset of symptoms, neurologic deterioration, and significant dysfunction of cranial nerves VII and VIII. We discuss a 40-year-old man who developed mild hearing loss and headaches over the course of a month before presenting with a large acutely hemorrhagic vestibular schwannoma. In addition, we review the current literature pertaining to this pathology., Case Presentation: A previously healthy 40-year-old man with a 1-month history of mild headaches, dizziness, and left-sided hearing loss, tinnitus, and facial numbness presented with the acute onset of severe headache, vomiting, complete left-sided hearing loss, and left-sided facial weakness. Computed tomography and magnetic resonance imaging revealed a 4.1 × 2.7 cm hemorrhagic mass in the left cerebellopontine angle most consistent with VS. The patient subsequently underwent a retrosigmoid craniotomy and resection of the tumor. Pathology was consistent with hemorrhagic VS. Imaging at 1-year follow-up demonstrated no residual or recurrent disease, and facial motor function had completely recovered., Conclusions: Histologically, vascular abnormalities and microhemorrhages are nearly ubiquitous across vestibular schwannomas and may contribute to cystic degeneration and rapid tumor growth. However, clinically significant hemorrhage is rarely encountered and is more commonly associated with more profound neurologic sequelae and cranial nerve VII dysfunction. Surgical resection at the time of presentation should be strongly considered to remove the risk of repeat hemorrhage and further deterioration. Our case represents a typical presentation and clinical course for a patient presenting with this rarely encountered pathology., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Background: Primary optic apparatus involvement by lymphoma is an exceedingly rare entity, with only 3 cases previously reported in the literature. Whether this represents a distinct pathology, metastatic disease from an unidentified systemic lymphoma, or the first manifestation of evolving primary central nervous system lymphoma is not currently understood., Case Description: We present a case of a young immunocompetent male with rapidly progressive visual loss who was found to have isolated lymphomatous involvement of the optic apparatus. We discuss the classification of the lesion, the clinical presentation, the diagnostic workup, and the visual and overall prognosis. Special consideration is given to the operative approach and selecting an appropriate site for biopsy based on the visual exam at the time of presentation., Conclusions: Primary optic nerve lymphoma is a rare disease that requires a systemic workup and a multidisciplinary approach to treatment., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Background: The role of 5-aminosalicylic acid (5-ASA or mesalamine) in the prevention of colorectal cancer in ulcerative colitis (UC) patients was reported, but the effect on molecular targets in UC colon mucosa is unknown., Aim: This observational study evaluates gene expression levels of 5-ASA targets using serial colon biopsy specimens from UC patients undergoing long-term 5-ASA therapy., Methods: Transcript levels were compared between colonoscopic biopsy specimens collected from 62 patients at initial and final follow-up colonoscopy at 2-6 years. All patients had mild-to-moderate UC and were undergoing long-term 5-ASA maintenance. Stepwise multiple linear regression analyses were performed to correlate changes in transcript levels with therapeutic response (Mayo clinical score endoscopy and DAI and/or Nancy histopathology score) and nonclinical variables., Results: The transcript levels of colorectal carcinogenesis-associated known 5-ASA target genes were significantly reduced after prolonged 5-ASA therapy (P < 0.005-0.03). Multiple linear regression models predicted significant association between transcript levels of Ki-67, NF-kB (p65), PPARγ, COX-2 and IL-8, CDC25A, and CXCL10 with duration of drug (5-ASA) exposure (P ≤ 0.05). Ki-67, NF-kB (p65), and CXCL10 transcripts were also correlated with reduced endoscopy sub-score (P ≤ 0.05). COX-2, IL-8, CDC25A, and TNF transcripts strongly correlated with DAI sub-scores (P ≤ 0.05). Only COX-2 and IL-8 transcript levels correlated (P ≤ 0.05) with Nancy histological score., Conclusion: This study provides molecular evidence of changes in carcinogenesis-related targets/pathways in colon tissue during long-term 5-ASA maintenance therapy that may contribute to the observed chemopreventive effects of 5-ASA in UC patients.

Background: MicroRNAs (miRNAs) are important post-translational regulators. Elevated levels of miR-206 in ulcerative colitis (UC) were associated with suppression of anti-inflammatory A3 adenosine receptor (A3AR) expression. However, the relationship of miR-206 to histologic remission in UC patients remains unknown. This study correlates expression levels of miR-206 with histologic remission in patients treated via long-term mesalamine treatment to identify a possible mode of action for this mainstay drug for UC., Methods: Expression of miR-206 and its target A3AR were analyzed in HT29 cell line before and after mesalamine treatment (2 mM) at different time points (0, 4, 12, and 24 hours) by qRT-PCR and western blot analysis. Expression of miR-206 and pathological scores of colonoscopic biopsy specimens were studied in 10 UC patients treated with mesalamine treatment for 2 to 6 years., Results: miR-206 transcripts decreased 2.23-fold (P = 0.0001) 4 hours after 2 mM mesalamine treatment in HT29 colon cells compared with untreated controls. However, the mRNA/protein levels of A3AR increased by 4-fold (P = 0.04) and 2-fold, respectively, in same cells. miR-206 relative expression decreased significantly in patients treated with 4.8 g of mesalamine (P = 0.002) but not with 2.4 g (P = 0.35). Tissue assessment of sequential mesalamine-treated colonoscopic biopsies indicate a strong correlation between downregulation of miR-206 and histologic improvement (R = 0.9111)., Conclusion: Mesalamine treatment has an effect on epithelial miRNAs. Downregulation of miR-206 by long-term mesalamine treatment may confer a protective effect in inducing and maintaining histologic remission. Thus, miR-206 expression levels can be utilized as a possible biomarker for therapeutic response to mesalamine treatment.

Background: Arteriovenous malformation (AVM)-associated aneurysms are common, reported in 15% of cases. Regarding the ruptured posterior fossa AVMs, associated aneurysms are present in 48% of cases and are the cause of the bleed in 37%. We present a 75-year-old female who presented with a subarachnoid hemorrhage secondary to a ruptured aneurysm arising from a flow-related basilar perforator artery feeder of an anterior pontine AVM. We report the successful treatment of the aneurysm with coil embolization., Case Description: A 75-year-old female presented with subarachnoid hemorrhage primarily contained within the posterior fossa. Angiography demonstrated a 2 × 3-mm fusiform aneurysm arising from a basilar perforator feeding pedicle of an anterior 1 × 2-cm pontine AVM. Venous drainage from the AVM was predominantly to the superior petrosal vein. Under roadmap guidance, super-selective catheterization of the basilar perforator aneurysm was performed. Three HydroSoft 3D coils were deployed within the aneurysm, resulting in complete obliteration. The patient was discharged on postbleed day 15 to an inpatient rehabilitation facility. Follow-up angiography at 5 months demonstrated stable complete obliteration. The patient made a complete recovery and was living independently at the time of this report., Conclusions: Basilar trunk perforator aneurysms are rare lesions, particularly in the setting of brainstem AVMs. We report successful endovascular treatment of a flow-related ruptured basilar perforator aneurysm associated with an anterior pontine AVM. To the best of our knowledge, this is the second report addressing this scenario. We hope that the information presented here serves to guide future surgical decision making and management., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Objective: Independent association of chronic kidney disease (CKD) and proliferative diabetic retinopathy (PDR) with cardiovascular disease (CVD) has not been established. In the Joslin 50-Year Medalist study, characterizing individuals with type 1 diabetes for 50 years or more, we examined the associations of CKD and PDR with CVD, which was validated by another cohort with type 1 diabetes from Finland., Research Design and Methods: This cross-sectional study characterized U.S. residents ( n = 762) with type 1 diabetes of 50 years or longer (Medalists) at a single site by questionnaire, clinical, ophthalmic, and laboratory studies. A replication cohort ( n = 675) from the longitudinal Finnish Diabetic Nephropathy Study (FinnDiane) was used. CKD and PDR were defined as estimated glomerular filtration rate <45 mL/min/1.73 m 2 (CKD stage 3b) and according to the Early Treatment Diabetic Retinopathy Study (ETDRS) protocol, respectively. CVD was based on questionnaires and/or hospital discharge registers. Associations of CVD status with CKD and PDR were analyzed by multivariable logistic regression., Results: CVD prevalence in the Medalists with CKD and without PDR (+CKD/-PDR) ( n = 30) and CVD prevalence in the -CKD/+PDR group ( n = 339) were half the prevalence in the +CKD/+PDR group ( n = 66) (34.5% and 42.8% vs. 68.2%, P = 0.002). PDR status was independently associated with CVD (odds ratio 0.21 [95% CI 0.08-0.58], P = 0.003) in patients with CKD. Among the Finnish cohort, a trend toward a lower prevalence of CVD in the +CKD/-PDR group ( n = 21) compared with the +CKD/+PDR group ( n = 170) (19.1% vs. 37.1%, P = 0.10) was also observed., Conclusions: Absence of PDR in people with type 1 diabetes and CKD was associated with a decreased prevalence of CVD, suggesting that common protective factors for PDR and CVD may exist., (© 2018 by the American Diabetes Association.)

Background: Intracranial aneurysms are the leading cause of nontraumatic subarachnoid hemorrhage and are most commonly associated with the anterior cerebral artery (ACA) and anterior communicating artery complex. We describe the presentation and management of a 27-year-old man with concurrent bilateral A1-2 junction aneurysms and fusiform intraorbital ophthalmic artery (OA) aneurysms., Case Description: A 27-year-old man with no past medical history presented with 3 months of headaches. Imaging showed a large dysplastic left A1-2 junction aneurysm and a smaller saccular right A1-2 junction aneurysm, with potentially adherent domes. Two fusiform aneurysms of the intraorbital segment of the left OA were also identified. The patient underwent coil-assisted pipeline embolization of the left A1-A2 aneurysm, with complete obliteration and reconstitution of the normal parent vessel. The patient underwent coil embolization of the right A1-2 aneurysm 3 weeks later, which was found to have grown significantly at the time of treatment. Three-month follow-up showed spontaneous resolution of the OA aneurysms, persistent obliteration of the left aneurysm, and significant recurrence of the right aneurysm, which was treated with stent-assisted coil embolization. A second recurrence 3 months later was successfully treated with repeat coiling. At the time of this treatment, the patient was also found to have 2 de novo distal middle cerebral artery and ACA dysplastic aneurysms, which were not treated. Follow-up angiography 6 weeks later showed stable complete obliteration of the right A1-2 aneurysm and interval complete resolution of the dysplastic middle cerebral artery aneurysm. The distal ACA aneurysm was observed to have minimally increased in size; however, the parent vessel showed signs of interval partial thrombosis with contrast stasis within the aneurysm. This final aneurysm is being followed with serial imaging. The patient remains neurologically intact with complete resolution of his headaches., Conclusions: We report the case of a young man with no past medical history who presented with multiple dysplastic aneurysms. Successful staged endovascular intervention resulted in obliteration of aneurysms with spontaneous obliteration of the intraorbital OA aneurysms observed at 3 months. We present this case to review the multiple challenges of managing complex ACA aneurysms and to highlight the usefulness of endovascular intervention in their treatment., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Diabetic nephropathy (DN) is a major cause of end-stage renal disease, and therapeutic options for preventing its progression are limited. To identify novel therapeutic strategies, we studied protective factors for DN using proteomics on glomeruli from individuals with extreme duration of diabetes (ł50 years) without DN and those with histologic signs of DN. Enzymes in the glycolytic, sorbitol, methylglyoxal and mitochondrial pathways were elevated in individuals without DN. In particular, pyruvate kinase M2 (PKM2) expression and activity were upregulated. Mechanistically, we showed that hyperglycemia and diabetes decreased PKM2 tetramer formation and activity by sulfenylation in mouse glomeruli and cultured podocytes. Pkm-knockdown immortalized mouse podocytes had higher levels of toxic glucose metabolites, mitochondrial dysfunction and apoptosis. Podocyte-specific Pkm2-knockout (KO) mice with diabetes developed worse albuminuria and glomerular pathology. Conversely, we found that pharmacological activation of PKM2 by a small-molecule PKM2 activator, TEPP-46, reversed hyperglycemia-induced elevation in toxic glucose metabolites and mitochondrial dysfunction, partially by increasing glycolytic flux and PGC-1α mRNA in cultured podocytes. In intervention studies using DBA2/J and Nos3 (eNos) KO mouse models of diabetes, TEPP-46 treatment reversed metabolic abnormalities, mitochondrial dysfunction and kidney pathology. Thus, PKM2 activation may protect against DN by increasing glucose metabolic flux, inhibiting the production of toxic glucose metabolites and inducing mitochondrial biogenesis to restore mitochondrial function.

Inflammatory processes are implicated in many diseases of the vasculature and have been shown to play a key role in the formation of intracranial aneurysms (IAs). Although the specific mechanisms underlying these processes have been thoroughly investigated in related pathologies, such as atherosclerosis, there remains a paucity of information regarding the immunopathology of IA. Cells such as macrophages and lymphocytes and their effector molecules have been suggested to be players in IA, but their specific interactions and the role of other components of the inflammatory response have yet to be determined. Drawing parallels between the pathogenesis of IA and other vascular disorders could provide a roadmap for developing a mechanistic understanding of the immunopathology of IA and uncovering useful targets for therapeutic intervention. Future research should address the presence and function of leukocyte subsets, mechanisms of leukocyte recruitment and activation, and the role of damage-associated molecular patterns in IA.

Background: Immunomodulatory therapies have been identified as interventions for secondary injury after traumatic brain injury (TBI). The cannabinoid receptor type-2 (CB2R) is proposed to play an important, endogenous role in regulating inflammation. The effects of CB2R stimulation, blockade, and deletion on the neurovascular inflammatory responses to TBI were assessed., Methods: Wild-type C57BL/6 or CB2R knockout mice were randomly assigned to controlled cortical impact (CCI) injury or to craniotomy control groups. The effects of treatment with synthetic, selective CB2R agonists (0-1966 and JWH-133), a selective CB2R antagonist, or vehicle solution administered to CCI groups were assessed at 1-day after injury. Changes in TNF-α, intracellular adhesion molecule (ICAM-1), inducible nitric oxide synthase (iNOS), macrophage/microglial ionized calcium-binding adaptor molecule, and blood-brain-barrier (BBB) permeability were assessed using ELISA, quantitative RT-PCR, immunohistochemistry, and fluorometric analysis of sodium fluorescein uptake. CB2R knockouts and wild-type mice with CCI injury were treated with a CB2R agonist or vehicle treatment., Results: TNF-α mRNA increased at 6 hours and 1 to 3 days after CCI; a CB2R antagonist and genetic knockout of the CB2R exacerbated TNF-α mRNA expression. Treatment with a CB2R agonist attenuated TNF-α protein levels indicating post-transcriptional mechanisms. Intracellular adhesion molecule (ICAM-1) mRNA was increased at 6 hours, and at 1 to 2 days after CCI, reduced in mice treated with a CB2R agonist, and increased in CB2R knockout mice with CCI. Sodium fluorescein uptake was increased in CB2R knockouts after CCI, with and without a CB2R agonist. iNOS mRNA expression peaked early (6 hours) and remained increased from 1 to 3 days after injury. Treatment with a CB2R agonist attenuated increases in iNOS mRNA expression, while genetic deletion of the CB2R resulted in substantial increases in iNOS expression. Double label immunohistochemistry confirmed that iNOS was expressed by macrophage/microglia in the injured cortex., Conclusion: Findings demonstrate that the endogenous cannabinoid system and CB2R play an important role in regulating inflammation and neurovascular responses in the traumatically injured brain. CB2R stimulation with two agonists (0-1966 and JWH-133) dampened post-traumatic inflammation, while blockade or deletion of the CB2R worsened inflammation. Findings support previous evidence that modulating the CB2R alters infiltrating macrophages and activated resident microglia. Further investigation into the role of the CB2R on specific immune cell populations in the injured brain is warranted.

Background: The reported incidence of concurrent traumatic brain (TBI) and spine or spinal cord injuries (SCI) is poorly defined, with widely variable literature rates from 16 to 74%., Objectives: To define the incidence of concurrent TBI and SCI, and compare the incidence over a twenty-year time period., Methods: To define the longitudinal incidence and concurrent rate of TBI and SCI via a retrospective review of the Nationwide Inpatient Sample (NIS) database over a twenty year period., Results: Over the study period, the incidence of TBI declined from 143 patients/100k admissions to 95 patients/100k. However, there was a concurrent increase in SCI from 61 patients/100k admissions to 75 patients/100k admissions (P<0.0001). Regional variations in SCI trends were noted, with specific regions demonstrating an increasing trend. Cervical fractures had the greatest increase by nearly a three-fold rise (1988: 4562-2008: 12,418). There was an increase in the incidence of TBI among SCI admission from 3.7% (1988) to 12.5% (2008) (OR=1.067 per year; 95% CI=1.065-1.069 per year; P<0.0001). Concurrently, SCI patients had an increase in TBI (9.1% (1988)-15.9% (2008) (OR=1.038 per year (95% CI 1.036-1.040; P<0.001)))., Conclusion: A retrospective review of the NIS demonstrates a rising trend in the incidence of concurrent TBI and SCI. More investigative work is necessary to examine causative factors for this trend., (Copyright © 2014 Elsevier B.V. All rights reserved.)

Helicobacter pylori (H. pylori) infection is well known to be associated with the development of precancerous lesions such as chronic atrophic gastritis (AG), or gastric intestinal metaplasia (GIM), and cancer. Various molecular alterations are identified not only in gastric cancer (GC) but also in precancerous lesions. H. pylori treatment seems to improve AG and GIM, but still remains controversial. In contrast, many studies, including meta-analysis, show that H. pylori eradication reduces GC. Molecular markers detected by genetic and epigenetic alterations related to carcinogenesis reverse following H. pylori eradication. This indicates that these changes may be an important factor in the identification of high risk patients for cancer development. Patients who underwent endoscopic treatment of GC are at high risk for development of metachronous GC. A randomized controlled trial from Japan concluded that prophylactic eradication of H. pylori after endoscopic resection should be used to prevent the development of metachronous GC, but recent retrospective studies did not show the tendency. Patients with precancerous lesions (molecular alterations) that do not reverse after H. pylori treatment, represent the "point of no return" and may be at high risk for the development of GC. Therefore, earlier H. pylori eradication should be considered for preventing GC development prior to the appearance of precancerous lesions.

Background: Cervical spondylotic myelopathy (CSM) is typically encountered in the elderly population. Significant inconsistencies currently exist regarding the definition of the disorder, the true incidence of CSM in younger populations, and the established diagnostic criteria., Objective: To highlight the lack of standardization in the definition and diagnosis of CSM., Methods: A PubMed literature search was conducted spanning the years 2001-2011. The search was limited by the following terms: (1) English language, (2) adults (19-44 years old), and (3) "cervical spondylotic myelopathy." Each article was reviewed to determine if the presence of the definition of CSM existed in the article. The clinical characteristics used to make the diagnosis of CSM were recorded for each article. Cochran's Q statistic was used to determine whether some clinical characteristics were more frequently used than others., Results: Ninety-three papers were reviewed in detail and 16 case reports, reviews, and articles concerning less than 3 patients were excluded, resulting in 77 articles in the final analysis. The most common clinical definitions were gait disturbance (22/77 articles (28.6%)), upper limb paresthesias or sensory disturbance (21/77 (27.3%)), and clumsy hands (15/77 (19.5%)). Hyperreflexia, spasticity, and pathologically increased reflexes were identified as diagnostic criteria in a minority of patients., Conclusion: The literature employs a wide range of neurologic signs and symptoms to make the diagnosis of CSM, with a majority of studies failing to rely on strict diagnostic criteria. The clinician should not discount CSM as an explanation for the aforementioned findings, as it is well-reported in the literature among the ages 18-44., (Copyright © 2014 Elsevier B.V. All rights reserved.)

The cerebellopontine angle is the site for a wide-range of neoplastic and vascular pathologies. The retrosigmoid craniotomy remains the primary means by which to gain surgical access to this anatomically complex region. We present our standard technique for the completion of a retrosigmoid craniotomy and the resection of a left-sided vestibular schwannoma. Anatomy pertinent to the approach, including, the transverse and sigmoid sinuses, cranial nerves, and internal auditory canal (IAC) is displayed. Special emphasis is placed on patient positioning, adequate bone removal, and tumor resection. The drilling of the IAC and tumor dissection from the VII-VIII complex is also highlighted. Hearing preservation was achieved. The video can be found here: http://youtu.be/FFZju5vcBi0 .

After traumatic brain injury (TBI), inflammation participates in both the secondary injury cascades and the repair of the CNS, both of which are influenced by the endocannabinoid system. This study determined the effects of repeated treatment with a cannabinoid type 2 receptor (CB(2) R) agonist on blood-brain barrier integrity, neuronal degeneration, and behavioral outcome in mice with TBI. We also looked for the presence of a prolonged treatment effect on the macrophage/microglial response to injury. C57BL/6 mice underwent controlled cortical impact (CCI) and received repeated treatments with a CB(2) R agonist, 0-1966, or vehicle. After euthanasia at 6 hr or 1, 2, 3, or 7 days postinjury, brains were removed for histochemical analysis. Blood-brain barrier permeability changes were evaluated by using sodium fluorescein (NaF). Perilesional degenerating neurons, injury volumes, and macrophage/microglia cells were quantified by stereological methods. Rota-rod and open-field testing were performed to evaluate motor function and natural exploratory behavior in mice. 0-1966 Treatment resulted in a significant reduction in NaF uptake and number of degenerating neurons compared with the vehicle-treated group. 0-1966-Treated mice demonstrated improvement on rota-rod and open-field testing compared with vehicle-treated mice. These changes in CCI mice treated with 0-1966 were associated with a prolonged reduction in macrophage/microglia cell counts. In conclusion, repeated treatments with a CB(2) R agonist, 0-1966, result in attenuated blood-brain barrier disruption and neuronal degeneration. In addition, repeated treatment with 0-1966 shows prolonged treatment effects on behavior and the macrophage/microglia cell response over several days., (Copyright © 2012 Wiley Periodicals, Inc.)

Intracranial vertebral artery dissection (VAD) represents the underlying etiology in a significant percentage of posterior circulation ischemic strokes and subarachnoid hemorrhages. These lesions are particularly challenging in their diagnosis, management, and in the prediction of long-term outcome. Advances in the understanding of underlying processes leading to dissection, as well as the evolution of modern imaging techniques are discussed. The data pertaining to medical management of intracranial VADs, with emphasis on anticoagulants and antiplatelet agents, is reviewed. Surgical intervention is discussed, including, the selection of operative candidates, open and endovascular procedures, and potential complications. The evolution of endovascular technology and techniques is highlighted.

Objective: This study tests the hypothesis that injury to the somatosensory cortex is associated with periorbital allodynia and increases in nociceptive neuropeptides in the brainstem in a mouse model of controlled cortical impact (CCI) injury., Methods: Male C57BL/6 mice received either CCI or craniotomy-only followed by weekly periorbital von Frey (mechanical) sensory testing for up to 28 days post-injury. Mice receiving an incision only and naïve mice were included as control groups. Changes in calcitonin gene-related peptide (CGRP) and substance P (SP) within the brainstem were determined using enzyme-linked immunosorbent assay and immunohistochemistry, respectively. Activation of ionized calcium-binding adaptor molecule-1-labeled macrophages/microglia and glial fibrillary acidic protein (GFAP)-positive astrocytes were evaluated using immunohistochemistry because of their potential involvement in nociceptor sensitization., Results: Incision-only control mice showed no changes from baseline periorbital von Frey mechanical thresholds. CCI significantly reduced mean periorbital von Frey thresholds (periorbital allodynia) compared with baseline and craniotomy-only at each endpoint, analysis of variance P < .0001. Craniotomy significantly reduced periorbital threshold at 14 days but not 7, 21, or 28 days compared with baseline threshold, P < .01. CCI significantly increased SP immunoreactivity in the brainstem at 7 and 14 days but not 28 days compared with craniotomy-only and controls, P < .001. CGRP levels in brainstem tissues were significantly increased in CCI groups compared with controls (incision-only and naïve mice) or craniotomy-only mice at each endpoint examined, P < .0001. There was a significant correlation between CGRP and periorbital allodynia (P < .0001, r = -0.65) but not for SP (r = 0.20). CCI significantly increased the number of macrophage/microglia in the injured cortex at each endpoint up to 28 days, although cell numbers declined over weeks post-injury, P < .001. GFAP(+) immunoreactivity was significantly increased at 7 but not 14 or 28 days after CCI, P < .001. Craniotomy resulted in transient periorbital allodynia accompanied by transient increases in SP, CGRP, and GFAP immunoreactivity compared with control mice. There was no increase in the number of macrophage/microglia cells compared with controls after craniotomy., Conclusion: Injury to the somatosensory cortex results in persistent periorbital allodynia and increases in brainstem nociceptive neuropeptides. Findings suggest that persistent allodynia and increased neuropeptides are maintained by mechanisms other than activation of macrophage/microglia or astrocyte in the injured somatosensory cortex., (© 2012 American Headache Society.)

Background: Stent-assisted coiling in the setting of subarachnoid hemorrhage remains controversial. Currently, there is a paucity of data regarding the utility of this procedure and the risks of hemorrhagic and ischemic complications., Objective: To assess the utility of stent-assisted coil embolization and pretreatment with antiplatelet agents in the management of ruptured wide-necked aneurysms., Methods: A retrospective study of 65 patients with ruptured wide-necked aneurysms treated with stent-assisted coiling. Patients with hydrocephalus or a Hunt and Hess grade ≥ III received a ventriculostomy before endovascular intervention. Patients were treated intraoperatively with 600 mg of clopidogrel and maintained on daily doses of 75 mg of clopidogrel and 81 mg of aspirin. The Glasgow outcome scale (GOS) score was recorded at the time of discharge. We identified major bleeding complications secondary to antiplatelet therapy and cases of in-stent thrombosis that required periprocedural thrombolysis., Results: Of the aneurysms, 66.2% arose within the anterior circulation; 69.2% of patients presented with hydrocephalus or a Hunt and Hess grade ≥ III and required a ventriculostomy. A good outcome (GOS of 4 or 5) was achieved in 63.1% of patients, and the overall mortality rate was 16.9%. There were 10 (15.38%) major complications associated with bleeding secondary to antiplatelet therapy (5 patients, 7.7%) or intraoperative in-stent thrombosis (5 patients, 7.7%). Three (4.6%) patients had a fatal hemorrhage., Conclusion: Our findings suggest that stent-assisted coiling and routine treatment with antiplatelet agents is a viable option in the management of ruptured wide-necked aneurysms.

Background: The risk factors predictive of intracranial aneurysm rupture remain incompletely defined., Objective: To examine the association between various nonmodifiable risk factors and aneurysm rupture in a large cohort of patients evaluated at a single institution., Methods: A retrospective analysis of patients admitted to a cerebrovascular facility between January 2006 and 2010 with a primary diagnosis of cerebral aneurysm. Aneurysms were divided into 2 groups: unruptured or ruptured. The dome diameter, aspect ratio (AR), location, sidedness, neck morphology, and multiplicity were entered into a central database. A full model was constructed, and a systematic removal of the least significant variables was performed in a sequential fashion until only those variables reaching significance remained., Results: We identified 2347 patients harboring 5134 individual aneurysms, of which 34.90% were ruptured and 65.09% were unruptured. On admission, 25.89% of aneurysms with a dome diameter <10 mm and 58.33% of aneurysms with a dome >10 mm were ruptured (P < .001). Of aneurysms with an AR >1.6, 52.44% presented following a rupture (P < .001). The highest incidence of rupture (69.21%) was observed in aneurysms with an AR >1.6, dome diameter <10 mm, and a deviated neck. Deviated neck-type aneurysms had a significantly greater incidence of rupture than classical neck-type aneurysms (P < .001)., Conclusion: An AR >1.6, dome diameter >10 mm, a deviated neck, and right-sidedness are independently associated with aneurysm rupture.