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Abstract TARGET POPULATIONS Adults with solid brain metastases who have not experienced a seizure. QUESTION 1 Do prophylactic antiepileptic drugs (AEDs) decrease the risk of seizures in nonsurgical patients with brain metastases who are otherwise seizure-free? RECOMMENDATION Level 3: Prophylactic AEDs are not recommended for patients with brain metastases who did not undergo surgical resection and are otherwise seizure-free. QUESTION 2 Do prophylactic AEDs decrease the risk of seizures in patients with brain metastases and no prior history of seizures in the postoperative setting? RECOMMENDATION Level 3: Routine postcraniotomy AED use for seizure-free patients with brain metastases is not recommended. The full guideline can be found at: https://www.cns.org/guidelines/guidelines-treatment-adults-metastatic-brain-tumors/chapter_8.

Abstract Large vessel occlusions (LVOs), variably defined as blockages of the proximal intracranial anterior and posterior circulation, account for approximately 24% to 46% of acute ischemic strokes. Commonly refractory to intravenous tissue plasminogen activator (tPA), LVOs place large cerebral territories at ischemic risk and cause high rates of morbidity and mortality without further treatment. Over the past few years, an abundance of high-quality data has demonstrated the efficacy of endovascular thrombectomy for improving clinical outcomes in patients with LVOs, transforming the treatment algorithm for affected patients. In this review, we discuss the epidemiology, pathophysiology, natural history, and clinical presentation of LVOs as a framework for understanding the recent clinical strides of the endovascular era. Video Abstract 10.1093/neuros/nyz042 Video Abstract 10.1093.neuros.nyz042 6045763607001

An estimated 20% of all patients with cancer will develop brain metastases, with the majority of brain metastases occurring in those with lung, breast and colorectal cancers, melanoma or renal cell carcinoma. Brain metastases are thought to occur via seeding of circulating tumour cells into the brain microvasculature; within this unique microenvironment, tumour growth is promoted and the penetration of systemic medical therapies is limited. Development of brain metastases remains a substantial contributor to overall cancer mortality in patients with advanced-stage cancer because prognosis remains poor despite multimodal treatments and advances in systemic therapies, which include a combination of surgery, radiotherapy, chemotherapy, immunotherapy and targeted therapies. Thus, interest abounds in understanding the mechanisms that drive brain metastases so that they can be targeted with preventive therapeutic strategies and in understanding the molecular characteristics of brain metastases relative to the primary tumour so that they can inform targeted therapy selection. Increased molecular understanding of the disease will also drive continued development of novel immunotherapies and targeted therapies that have higher bioavailability beyond the blood–tumour barrier and drive advances in radiotherapies and minimally invasive surgical techniques. As these discoveries and innovations move from the realm of basic science to preclinical and clinical applications, future outcomes for patients with brain metastases are almost certain to improve. An estimated 20% of all patients with cancer will develop brain metastases, with the majority of brain metastases occurring in those with lung and breast cancer and melanoma. This Primer describes the mechanisms by which cancer cells migrate to the brain and the key advances necessary to improve the prognosis for patients with brain metastases.

Significance Diabetes is the leading cause of nontraumatic amputations. There are no effective therapies to prevent diabetic ulcer formation and only modestly effective technologies to help with their healing. To enhance diabetic wound healing we designed a transdermal delivery system containing the FDA-approved small molecule deferoxamine, an iron chelator that increases defective hypoxia inducible factor-1 alpha transactivation in diabetes by preventing iron-catalyzed reactive oxygen stress. This system overcomes the challenge of delivering hydrophilic molecules through the normally impermeable stratum corneum and both prevents diabetic ulcer formation and improves the healing of existing diabetic wounds. This represents a prophylactic pharmacological agent to prevent ulcer formation that is rapidly translatable into the clinic and has the potential to ultimately transform the care and prevention of diabetic complications. There is a high mortality in patients with diabetes and severe pressure ulcers. For example, chronic pressure sores of the heels often lead to limb loss in diabetic patients. A major factor underlying this is reduced neovascularization caused by impaired activity of the transcription factor hypoxia inducible factor-1 alpha (HIF-1α). In diabetes, HIF-1α function is compromised by a high glucose-induced and reactive oxygen species-mediated modification of its coactivator p300, leading to impaired HIF-1α transactivation. We examined whether local enhancement of HIF-1α activity would improve diabetic wound healing and minimize the severity of diabetic ulcers. To improve HIF-1α activity we designed a transdermal drug delivery system (TDDS) containing the FDA-approved small molecule deferoxamine (DFO), an iron chelator that increases HIF-1α transactivation in diabetes by preventing iron-catalyzed reactive oxygen stress. Applying this TDDS to a pressure-induced ulcer model in diabetic mice, we found that transdermal delivery of DFO significantly improved wound healing. Unexpectedly, prophylactic application of this transdermal delivery system also prevented diabetic ulcer formation. DFO-treated wounds demonstrated increased collagen density, improved neovascularization, and reduction of free radical formation, leading to decreased cell death. These findings suggest that transdermal delivery of DFO provides a targeted means to both prevent ulcer formation and accelerate diabetic wound healing with the potential for rapid clinical translation.

Management options for refractory intracranial atherosclerotic disease (ICAD) involve intracranial stenting or bypass. By retrospectively analyzing National Inpatient Sample database data (2012–2019), we compared costs, complications, length of stay (LOS), and discharge disposition of patients who underwent elective intracranial stenting or bypass for ICAD. Analyses included propensity score matching (PSM; 1:1), multilevel mixed-effects generalized linear models, and logistic regression. Overall, 556 admissions were included (mean age 65.2 years). Patients undergoing bypass were more likely than stenting patients to be female (47.3% vs. 37.5%, p  = 0.028) and to have a Charlson Comorbidity Index score ≥ 2 (77.2% vs. 61.5%, p  < 0.001) but less likely to have a history of transient ischemic attack/stroke (52.2 vs. 62.0%, p  = 0.027). PSM yielded a subset of 330 patients (165 stenting, 165 bypass). The unadjusted cost of bypass admissions exceeded that of stent admissions (mean $24,659 vs. $20,750, p  = 0.056), driven by significantly longer LOS for bypass (B = 1.69, p  < 0.001). There were no significant differences in the odds of complications or adverse discharge by treatment ( p  > 0.05). These data suggest that for patients with ICAD undergoing an elective intervention, bypass and stenting have largely comparable overall costs and short-term outcomes. Treatment for refractory ICAD should be individualized based on patient and clinical criteria.

Background Craniocervical junction (CCJ) vascular abnormalities can be challenging to treat because of the surrounding density of critical neurovascular anatomy. Although most dural arteriovenous fistulas (dAVFs) are now treated with endovascular surgery, dAVFs near the CCJ are often better suited for microsurgical obliteration with precise vascular control. Methods We describe our microsurgical approach to treating dAVFs at the CCJ. This includes a far-lateral approach with a small incision centered over the transverse process of the atlas and circumferential skeletonization of the vertebral artery in addition to clipping the fistula to limit lesion recurrence. Conclusions Definitive microsurgical treatment of CCJ dAVFs can be accomplished using a minimally invasive approach.

Scarring and tissue fibrosis represent a significant source of morbidity in the United States. Despite considerable research focused on elucidating the mechanisms underlying cutaneous scar formation, effective clinical therapies are still in the early stages of development. A thorough understanding of the various signaling pathways involved is essential to formulate strategies to combat fibrosis and scarring. While initial efforts focused primarily on the biochemical mechanisms involved in scar formation, more recent research has revealed a central role for mechanical forces in modulating these pathways. Mechanotransduction, which refers to the mechanisms by which mechanical forces are converted to biochemical stimuli, has been closely linked to inflammation and fibrosis and is believed to play a critical role in scarring. This review provides an overview of our current understanding of the mechanisms underlying scar formation, with an emphasis on the relationship between mechanotransduction pathways and their therapeutic implications.

Background Dural arteriovenous fistulas (dAVFs) at the superior petrosal sinus are a rare but important subtype that pose a high risk of mortality and morbidity. Treatment for these lesions can be challenging with stand-alone endovascular methods. Methods We describe our “in-out-in” technique for disconnecting dAVFs at the superior petrosal sinus, which includes definitive sacrifice of the superior petrosal sinus and the transverse sigmoid sinus, if involved. This method achieves complete fistula obliteration and minimizes recurrence risk with new arterial feeders. Conclusions The in-out-in technique is a safe and effective approach for the treatment of dAVFs involving the superior petrosal sinus.

Background Defects through the skull base into the paranasal sinuses can occur during anterior skull base procedures, risking cerebrospinal fluid leak and infection if not repaired. Methods We describe a muscle plug napkin ring technique for closure of small skull base defects, wherein a free muscle graft slightly bigger than the defect is packed tightly in the defect, half extracranially and half intracranially and sealed with fibrin glue. The technique is illustrated in the case of a 58-year-old woman with a large left medial sphenoid wing/clinoidal meningioma. Conclusions The muscle plug napkin ring technique is a simple solution to small skull base defects.