Management of moyamoya disease: a review of current and future therapeutic strategies.

Moyamoya disease (MMD) is characterized by idiopathic, progressive stenosis of the circle of Willis and the terminal portion of the internal carotid arteries with the development of prominent small collateral vessels and a characteristic moyamoya or puff-of-smoke radiographic appearance. The incidence and prevalence of MMD varies by region, age, and sex, with higher rates in Asian and East Asian populations compared to North American or European populations. There is a bimodal distribution of patients diagnosed with MMD. Pediatric patients are more commonly diagnosed within the 1st decade of life, whereas adult patients present in the 5th or 6th decade of life. Overall, there is a nearly 2:1 female-to-male ratio. Ischemic symptoms are the most common presentation in pediatric and adult populations, but adult patients are nearly twice as likely to present with intracranial hemorrhage compared to their pediatric counterparts. Surgical revascularization is indicated in symptomatic cases, and antiplatelet therapy may be a useful adjunct to prevent recurrent symptoms. Direct and combined bypass procedures seem to be more effective in adults, whereas children respond well to indirect bypass. The identification of key genetic, molecular, and environmental factors including RNF213 and GUCY1A3 loss-of-function mutations, angiogenic growth factors, autoantibodies, CNS infections, and radiation exposure suggest multiple pathways for the development of moyamoya arteriopathy. Further research is needed to better understand the heterogeneity of pathogenetic mechanisms that lead to moyamoya and to identify novel therapeutic targets to prevent, stabilize, and treat MMD.

Endovascular Applications for the Management of High-Grade Gliomas in the Modern Era.

High-grade gliomas (HGGs) have a poor prognosis and are difficult to treat. This review examines the evolving landscape of endovascular therapies for HGGs. Recent advances in endovascular catheter technology and delivery methods allow for super-selective intra-arterial cerebral infusion (SSIACI) with increasing precision. This treatment modality may offer the ability to deliver anti-tumoral therapies directly to tumor regions while minimizing systemic toxicity. However, challenges persist, including blood-brain barrier (BBB) penetration, hemodynamic complexities, and drug-tumor residence time. Innovative adjunct techniques, such as focused ultrasound (FUS) and hyperosmotic disruption, may facilitate BBB disruption and enhance drug penetration. However, hemodynamic factors that limit drug residence time remain a limitation. Expanding therapeutic options beyond chemotherapy, including radiotherapy and immunobiologics, may motivate future investigations. While preclinical and clinical studies demonstrate moderate efficacy, larger randomized trials are needed to validate the clinical benefits. Additionally, future directions may involve endovascular sampling for peri-tumoral surveillance; changes in drug formulations to prolong residence time; and the exploration of non-pharmaceutical therapies, like radioembolization and photodynamic therapy. Endovascular strategies hold immense potential in reshaping HGG treatment paradigms, offering targeted and minimally invasive approaches. However, overcoming technical challenges and validating clinical efficacy remain paramount for translating these advancements into clinical care.

Incidence and Risk Model of Post-Traumatic Hydrocephalus in Patients with Traumatic Brain Injury.

OBJECTIVE: Post-traumatic hydrocephalus (PTH) is a complication following traumatic brain injury (TBI). Early diagnosis and treatment are essential to improving outcomes. We report the incidence and risk factors of PTH in a large TBI population while considering death as a competing risk. METHODS: We conducted a retrospective cohort study on consecutive TBI patients with radiographic intracranial abnormalities admitted to our academic medical center from 2009 to 2015. We assessed patient demographics, perioperative data, and in-hospital data as risk factors for PTH using survival analysis with death as a competing risk. RESULTS: Among 7,473 patients, the overall incidence of PTH requiring shunt surgery was 0.94%. The adjusted cumulative incidence was 0.99%. The all-cause cumulative hazard for death was 32.6%, which was considered a competing risk during analysis. Craniectomy (HR 11.53, P < 0.001, 95% CI 5.57-223.85), venous sinus injury (HR 4.13, P = 0.01, 95% CI 1.53-11.16), and age ≤5 (P < 0.001) were significant risk factors for PTH. Glasgow Coma Score (GCS) > 13 was protective against shunt placement (HR 0.50, P = 0.04, 95% CI 0.26-0.97). Shunt surgery occurred after hospital discharge in 60% of patients. CONCLUSIONS: We describe the incidence and risk factors for PTH in a large traumatic brain injury (TBI) population. Most cases of PTH were diagnosed after hospital discharge, suggesting that close follow-up and multidisciplinary diagnostic vigilance for PTH are needed to prevent morbidity and disability.

Deep Brain Stimulation of Bilateral Centromedian Thalamic Nuclei in Pediatric Patients with Lennox-Gastaut Syndrome: An Institutional Experience.

BACKGROUND: Surgical management of pediatric patients with nonlesional, drug-resistant epilepsy, including patients with Lennox-Gastaut syndrome (LGS), remains a challenge given the lack of resective targets in most patients and shows seizure freedom rates <50% at 5 years. The efficacy of deep brain stimulation (DBS) is less certain in children than in adults. This study examined clinical and seizure outcomes for pediatric patients with LGS undergoing DBS targeting of the centromedian thalamic nuclei (CMTN). METHODS: An institutional review board-approved retrospective analysis was performed of patients aged ≤19 years with clinical diagnosis of LGS undergoing bilateral DBS placement to the CMTN from 2020 to 2021 by a single surgeon. RESULTS: Four females and 2 males aged 6-19 years were identified. Before surgery, each child experienced at least 6 years of refractory seizures; 4 children had experienced seizures since infancy. All took antiseizure medications at the time of surgery. Five children had previous placement of a vagus nerve stimulator and 2 had a previous corpus callosotomy. The mean length of stay after DBS was 2 days. No children experienced adverse neurologic effects from implantation; the mean follow-up time was 16.3 months. Four patients had >60% reduction in seizure frequency after surgery, 1 patient experienced 10% reduction, and 1 patient showed no change. No children reported worsening seizure symptoms after surgery. CONCLUSIONS: Our study contributes to the sparse literature describing CMTN DBS for children with drug-resistant epilepsy from LGS. Our results suggest that CMTN DBS is a safe and effective therapeutic modality that should be considered as an alternative or adjuvant therapy for this challenging patient population. Further studies with larger patient populations are warranted.

Combination endovascular and microsurgical treatment of partially thrombosed ruptured ICA terminus aneurysm, with common carotid artery to MCA bypass via saphenous vein graft and parent vessel sacrifice after coil embolization.

A 63-year-old woman presented with ruptured giant ICA terminus aneurysm, temporized with coil embolization and definitively treated with parent vessel sacrifice and high-flow bypass.

Craniocervical dural arteriovenous fistula: Microsurgical clipping and technical nuances with ICG.

A 48-year-old male with progressive congestive myelopathy had a craniocvervical DAVF treated with surgical clipping using ICG to confirm solitary inflow.

Brain AVM surgery without endovascular embolization in a low to middle income country.

We treated a 20-year-old woman in Paraguay with a ruptured intraventricular Spetzler-Martin Grade 3 AVM, and illustrate microsurgical resection without embolization in this video.

Operative Technique and Complication Management in a Case of Giant Esthesioneuroblastoma Resected by a Combined Transcranial and Endonasal Endoscopic Approach: Technical Case Report.

BACKGROUND AND IMPORTANCE: Esthesioneuroblastoma (ENB) is a rare anterior skull base tumor derived from olfactory epithelium. There are very few operative videos in the literature demonstrating the surgical resection techniques for giant ENB because of their rarity and complexity. In this technical report, we demonstrate the microsurgical resection of a very large and complex high-grade ENB, initially deemed unresectable, through a bifrontal craniotomy and extended subfrontal approach combined with an endonasal endoscopic approach. CLINICAL PRESENTATION: A 34-year-old woman presented with headaches, nasal congestion, and bloody nasal drainage. MRI showed a large nasal cavity mass with extension into the anterior cranial fossa and bifrontal lobes. There was significant bifrontal edema causing headaches and abutting the optic nerves. Initial management with surgical resection was offered to the patient for local tumor control and to preserve her vision. A combined bifrontal craniotomy and endonasal transsphenoidal approach was used for resecting this giant tumor. After achieving gross total resection, we reconstructed the anterior skull base in layers. She developed several postoperative complications which were appropriately managed. CONCLUSION: We demonstrate the surgical resection of a giant ENB through a combined transcranial and endonasal endoscopic approach. We discuss the several postoperative complications in this complex case and the lessons learned.

Clopidogrel hyper-response increases peripheral hemorrhagic complications without increasing intracranial complications in endovascular aneurysm treatments requiring dual antiplatelet therapy.

Clinical significance of increased clopidogrel response measured by VerifyNow P2Y12 assay is unclear; management guidelines are lacking in the context of neuroendovascular intervention. Our objective was to assess whether increased clopidogrel response predicts complications from endovascular aneurysm treatment requiring dual antiplatelet therapy. A single-institution, 9-year retrospective study of patients undergoing endovascular treatments for ruptured and unruptured aneurysms requiring aspirin and clopidogrel was conducted. Patients were grouped according to preoperative platelet inhibition in response to clopidogrel measured by the VerifyNow P2Y12 assay (VNP; P2Y12 reactivity units, PRU). Demographic and clinical features were compared across groups. Hemorrhagic complication rates (intracranial, major extracranial, minor extracranial) and thromboembolic complications (in-stent stenosis, stroke/transient ischemic attack) were compared, controlling for potential confounders and multiple comparisons. Data were collected from 284 patients across 317 procedures. Pre-operative VNP assays identified 9 % Extreme Responders (PRU ≤ 15), 13 % Hyper-Responders (PRU 16-60), 62 % Therapeutic Responders (PRU 61-214), 16 % Hypo-Responders (PRU ≥ 215). Increased response to clopidogrel was associated with increased risk of any hemorrhagic complication (≤60 PRU vs > 60 PRU; 39 % vs 24 %, P = 0.050); all intracranial hemorrhages occurred in patients with PRU > 60. Thromboembolic complications were similar between therapeutic and subtherapeutic patients (<215 PRU vs ≥ 215 PRU; 15 % vs 16 %, P = 0.835). Increased preoperative clopidogrel response is associated with increased rate of extracranial hemorrhagic complications in endovascular aneurysm treatments. Hyper-responders (16-60 PRU) and Extreme Responders (≤15 PRU) were not associated with intracranial hemorrhagic or thrombotic complications. Hypo-responders who underwent adjustment of antiplatelet therapy and neurointerventions did not experience higher rates of complications.

A single-cell based precision medicine approach using glioblastoma patient-specific models.

Glioblastoma (GBM) is a heterogeneous tumor made up of cell states that evolve over time. Here, we modeled tumor evolutionary trajectories during standard-of-care treatment using multi-omic single-cell analysis of a primary tumor sample, corresponding mouse xenografts subjected to standard of care therapy, and recurrent tumor at autopsy. We mined the multi-omic data with single-cell SYstems Genetics Network AnaLysis (scSYGNAL) to identify a network of 52 regulators that mediate treatment-induced shifts in xenograft tumor-cell states that were also reflected in recurrence. By integrating scSYGNAL-derived regulatory network information with transcription factor accessibility deviations derived from single-cell ATAC-seq data, we developed consensus networks that modulate cell state transitions across subpopulations of primary and recurrent tumor cells. Finally, by matching targeted therapies to active regulatory networks underlying tumor evolutionary trajectories, we provide a framework for applying single-cell-based precision medicine approaches to an individual patient in a concurrent, adjuvant, or recurrent setting.

Three Column Cervical Fracture-Dislocation in a 3-Year-Old Boy.

Complete traumatic cervical fracture-dislocation with spinal cord transection in children is a rare entity with no evidence-based guidelines on management. The authors reviewed the literature for pediatric spinal cord injury and present the case of a 3-year-old with traumatic cervical fracture-dislocation and spinal cord transection who presented as a cervical-6 complete spinal cord injury (ASIA A). His other organ systems injured included liver, spleen, bowel, and abdominal aortic injury. The patient underwent halo placement for preoperative reduction followed by open reduction and internal fixation with posterior segmental instrumented fusion. Intraoperatively, the patient had motor evoked potential signals present below the level of his injury. Early postoperative follow-up demonstrated that, although his leg function did not improve, he did demonstrate improvement in upper extremities. This is a rare case of complete cervical spinal cord transection in a pediatric patient. We elected to manage this challenging case with initial external reduction and orthosis with a halo vest followed by acute posterior cervical fusion. Despite a cervical-6 injury level on clinical exam, there was electrographic evidence of function below that level on intraoperative neuromonitoring. Postoperatively the patient has recovered some lost function.

Prognostic Value of Hemorrhagic Brainstem Injury on Early Computed Tomography: A TRACK-TBI Study.

BACKGROUND: Traumatic brainstem injury has yet to be incorporated into widely used imaging classification systems for traumatic brain injury (TBI), and questions remain regarding prognostic implications for this TBI subgroup. To address this, retrospective data on patients from the multicenter prospective Transforming Research and Clinical Knowledge in TBI study were studied. METHODS: Patients with brainstem and cerebrum injury (BSI+) were matched by age, sex, and admission Glasgow Coma Scale (GCS) score to patients with cerebrum injuries only. All patients had an interpretable head computed tomography (CT) scan from the first 48 hours after injury and a 6-month Glasgow Outcome Scale Extended (GOSE) score. CT scans were reviewed for brainstem lesions and, when present, characterized by location, size, and type (traumatic axonal injury, contusion, or Duret hemorrhage). Clinical, demographic, and outcome data were then compared between the two groups. RESULTS: Mann-Whitney U-tests showed no significant difference in 6-month GOSE scores in patients with BSI+ (mean 2.7) compared with patients with similar but only cerebrum injuries (mean 3.9), although there is a trend (p = 0.10). However, subclassification by brainstem lesion type, traumatic axonal injury (mean 4.0) versus Duret hemorrhage or contusion (mean 1.4), did identify a proportion of BSI+ with significantly less favorable outcome (p = 0.002). The incorporation of brainstem lesion type (traumatic axonal injury vs. contusion/Duret), along with GCS into a multivariate logistic regression model of favorable outcome (GOSE score 4-8) did show a significant contribution to the prognostication of this brainstem injury subgroup (odds ratio 0.08, 95% confidence interval 0.00-0.67, p = 0.01). CONCLUSIONS: These findings suggest two groups of patients with brainstem injuries may exist with divergent recovery potential after TBI. These data support the notion that newer CT imaging classification systems may augment traditional clinical measures, such as GCS in identifying those patients with TBI and brainstem injuries that stand a higher chance of favorable outcome.

A Systems Approach to Brain Tumor Treatment.

Brain tumors are among the most lethal tumors. Glioblastoma, the most frequent primary brain tumor in adults, has a median survival time of approximately 15 months after diagnosis or a five-year survival rate of 10%; the recurrence rate is nearly 90%. Unfortunately, this prognosis has not improved for several decades. The lack of progress in the treatment of brain tumors has been attributed to their high rate of primary therapy resistance. Challenges such as pronounced inter-patient variability, intratumoral heterogeneity, and drug delivery across the blood-brain barrier hinder progress. A comprehensive, multiscale understanding of the disease, from the molecular to the whole tumor level, is needed to address the intratumor heterogeneity resulting from the coexistence of a diversity of neoplastic and non-neoplastic cell types in the tumor tissue. By contrast, inter-patient variability must be addressed by subtyping brain tumors to stratify patients and identify the best-matched drug(s) and therapies for a particular patient or cohort of patients. Accomplishing these diverse tasks will require a new framework, one involving a systems perspective in assessing the immense complexity of brain tumors. This would in turn entail a shift in how clinical medicine interfaces with the rapidly advancing high-throughput (HTP) technologies that have enabled the omics-scale profiling of molecular features of brain tumors from the single-cell to the tissue level. However, several gaps must be closed before such a framework can fulfill the promise of precision and personalized medicine for brain tumors. Ultimately, the goal is to integrate seamlessly multiscale systems analyses of patient tumors and clinical medicine. Accomplishing this goal would facilitate the rational design of therapeutic strategies matched to the characteristics of patients and their tumors. Here, we discuss some of the technologies, methodologies, and computational tools that will facilitate the realization of this vision to practice.

United States Medicolegal Progress and Innovation in Telemedicine in the Age of COVID-19: A Primer for Neurosurgeons.

Telemedicine has received increased attention in recent years as a potential solution to expand clinical capability and patient access to care in many fields, including neurosurgery. Although patient and physician attitudes are rapidly shifting toward greater telemedicine use in light of the COVID-19 pandemic, there remains uncertainty about telemedicine's regulatory future. Despite growing evidence of telemedicine's utility, there remain a number of significant medicolegal barriers to its mass adoption and wider implementation. Herein, we examine recent progress in state and federal regulations in the United States governing telemedicine's implementation in quality of care, finance and billing, privacy and confidentiality, risk and liability, and geography and interstate licensure, with special attention to how these concern teleneurosurgical practice. We also review contemporary topics germane to the future of teleneurosurgery, including the continued expansion of reciprocity in interstate licensure, expanded coverage for homecare services for chronic conditions, expansion of Center for Medicare and Medicaid Services reimbursements, and protections of store-and-forward technologies. Additionally, we discuss recent successes in teleneurosurgery, stroke care, and rehabilitation as models for teleneurosurgical best practices. As telemedicine technology continues to mature and its expanse grows, neurosurgeons' familiarity with its benefits, limitations, and controversies will best allow for its successful adoption in our field to maximize patient care and outcomes.

Impact of surgeon rhBMP-2 cost awareness on complication rates and health system costs for spinal arthrodesis.

OBJECTIVE: Recombinant human bone morphogenetic protein-2 (rhBMP-2) is used in spinal arthrodesis procedures to enhance bony fusion. Research has suggested that it is the most cost-effective fusion enhancer, but there are significant upfront costs for the healthcare system. The primary objective of this study was to determine whether intraoperative dosing and corresponding costs changed with surgeon cost awareness. The secondary objective was to describe surgical complications before and after surgeon awareness of rhBMP-2 cost. METHODS: A retrospective medical record review was conducted to identify patients who underwent spinal arthrodesis procedures performed by a single surgeon, supplemented with rhBMP-2, from June 2016 to June 2018. Collected data included rhBMP-2 dosage, rhBMP-2 list price, and surgical complications. Expected Medicare reimbursement was calculated. Data were analyzed before and after surgeon awareness of rhBMP-2 cost. RESULTS: Forty-eight procedures were performed using rhBMP-2, 16 before and 32 after surgeon cost awareness. Prior to cost awareness, the most frequent rhBMP-2 dosage level was x-small (38.9%, n = 7), followed by large (27.8%, n = 5) and small (22.2%, n = 4). After cost awareness, the most frequent rhBMP-2 dosage was xx-small (56.8%, n = 21), followed by x-small (21.6%, n = 8) and large (13.5%, n = 5). The rhBMP-2 average cost per surgery was $4116.56 prior to surgeon cost awareness versus $2268.38 after. Two complications were observed in the pre-cost awareness surgical group; 2 complications were observed in the post-cost awareness surgical group. CONCLUSIONS: Surgeon awareness of rhBMP-2 cost resulted in use of smaller rhBMP-2 doses, decreased rhBMP-2 cost per surgery, and decreased overall hospital admission charges, without a detectable increase in surgical complications.

Cellular allograft for multilevel stand-alone anterior cervical discectomy and fusion.

OBJECTIVE: Anterior cervical discectomy and fusion (ACDF) is the most common treatment for degenerative disease of the cervical spine. Given the high rate of pseudarthrosis in multilevel stand-alone ACDF, there is a need to explore the utility of novel grafting materials. In this study, the authors present a single-institution retrospective study of patients with multilevel degenerative spine disease who underwent multilevel stand-alone ACDF surgery with or without cellular allograft supplementation. METHODS: In a prospectively collected database, 28 patients who underwent multilevel ACDF supplemented with cellular allograft (ViviGen) and 25 patients who underwent multilevel ACDF with decellularized allograft between 2014 and 2020 were identified. The primary outcome was radiographic fusion determined by a 1-year follow-up CT scan. Secondary outcomes included change in Neck Disability Index (NDI) scores and change in visual analog scale scores for neck and arm pain. RESULTS: The study included 53 patients with a mean age of 53 ± 0.7 years who underwent multilevel stand-alone ACDF encompassing 2.6 ± 0.7 levels on average. Patient demographics were similar between the two cohorts. In the cellular allograft cohort, 2 patients experienced postoperative dysphagia that resolved by the 3-month follow-up. One patient developed cervical radiculopathy due to graft subsidence and required a posterior foraminotomy. At the 1-year CT, successful fusion was achieved in 92.9% (26/28) of patients who underwent ACDF supplemented with cellular allograft, compared with 84.0% (21/25) of patients who underwent ACDF without cellular allograft. The cellular allograft cohort experienced a significantly greater improvement in the mean postoperative NDI score (p < 0.05) compared with the other cohort. CONCLUSIONS: Cellular allograft is a low-morbidity bone allograft option for ACDF. In this study, the authors determined favorable arthrodesis rates and functional outcomes in a complex patient cohort following multilevel stand-alone ACDF supplemented with cellular allograft.

The Kempe incision for decompressive craniectomy, craniotomy, and cranioplasty in traumatic brain injury and stroke.

OBJECTIVE: Decompressive craniectomy (DC) is an effective, lifesaving option for reducing intracranial pressure (ICP) in traumatic brain injury (TBI), stroke, and other pathologies with elevated ICP. Most DCs are performed via a standard trauma flap shaped like a reverse question mark (RQM), which requires sacrificing the occipital and posterior auricular arteries and can be complicated by wound dehiscence and infections. The Ludwig Kempe hemispherectomy incision (Kempe) entails a T-shaped incision, one limb from the midline behind the hairline to the inion and the other limb from the root of the zygoma to the coronal suture. The authors' objective in this study was to define their implementation of the Kempe incision for DC and craniotomy, report clinical outcomes, and quantify the volume of bone removed compared with the RQM incision. METHODS: A retrospective review of a single-surgeon experience with DC in TBI and stroke was performed. Patient demographics, imaging, and outcomes were collected for all DCs from 2015 to 2020, and the incisions were categorized as either Kempe or RQM. Preoperative and postoperative CT scans were obtained and processed using a combination of automatic segmentation (in Python and SimpleITK) with manual cleanup and further subselection in ITK-SNAP. The volume of bone removed was quantified, and the primary outcome was percentage of hemicranium removed. Postoperative surgical wound infections, estimated blood loss (EBL), and length of surgery were compared between the two groups as secondary outcomes. Cranioplasty data were collected. RESULTS: One hundred thirty-six patients were included in the analysis; there were 57 patients in the craniotomy group (44 patients with RQM incisions and 13 with Kempe incisions) and 79 in the craniectomy group (41 patients with RQM incisions and 38 Kempe incisions). The mean follow-up for the entire cohort was 251 ± 368 days. There was a difference in the amount of decompression between approaches in multivariate modeling (39% ± 11% of the hemicranium was removed via the Kempe incision vs 34% ± 10% via the RQM incision, p = 0.047), although this did not achieve significance in multivariate modeling. Wound infection rates, EBL, and length of surgery were comparable between the two incision types. No wound infections in either cohort were due to wound dehiscence. Cranioplasty outcomes were comparable between the two incision types. CONCLUSIONS: The Kempe incision for craniectomy or craniotomy is a safe, feasible, and effective alternative to the RQM. The authors advocate the Kempe incision in cases in which contralateral operative pathology or subsequent craniofacial/skull base repair is anticipated.

Re-examining decompressive craniectomy medial margin distance from midline as a metric for calculating the risk of post-traumatic hydrocephalus.

Decompressive craniectomy (DC) is a life-saving procedure in severe traumatic brain injury, but is associated with higher rates of post-traumatic hydrocephalus (PTH). The relationship between the medial craniectomy margin's proximity to midline and frequency of developing PTH is controversial. The primary study objective was to determine whether average medial craniectomy margin distance from midline was closer to midline in patients who developed PTH after DC for severe TBI compared to patients that did not. The secondary objective was to determine if a threshold distance from midline could be identified, at which the risk of developing PTH increased if the DC was performed closer to midline than this threshold. A retrospective review was performed of 380 patients undergoing DC at a single institution between March 2004 and November 2014. Clinical, operative and demographic variables were collected, including age, sex, DC parameters and occurrence of PTH. Statistical analysis compared mean axial craniectomy margin distance from midline in patients with versus without PTH. Distances from midline were tested as potential thresholds. No significant difference was identified in mean axial craniectomy margin distance from midline in patients developing PTH compared with patients with no PTH (n = 24, 12.8 mm versus n = 356, 16.6 mm respectively, p = 0.086). No significant cutoff distance from midline was identified (n = 212, p = 0.201). This study, the largest to date, was unable to identify a threshold with sufficient discrimination to support clinical recommendations in terms of DC margins with regard to midline, including thresholds reportedly significant in previously published research.