Yield of genetic evaluation in non-syndromic pediatric moyamoya patients.

PURPOSE: Few guidelines exist for genetic testing of patients with moyamoya arteriopathy. This study aims to characterize the yield of genetic testing of non-syndromic moyamoya patients given the current pre-test probability. METHODS: All pediatric moyamoya patients who received revascularization surgery at one institution between 2018 and 2022 were retrospectively reviewed. Patients with previously diagnosed moyamoya syndromes or therapeutic cranial radiation were excluded. RESULTS: Of 117 patients with moyamoya, 74 non-syndromic patients (44 females, 59%) were eligible. The median age at surgery was 8.1 years. Neurosurgeons referred 18 (24%) patients for neurogenetic evaluation. Eleven (61%) patients subsequently underwent genetic testing. Eight (73%) patients had available testing results. Five (62.5%) of these patients had developmental delay compared to 16 (22%) of the entire cohort. Six (75%) patients who underwent genetic testing were found to have at least one genetic variant. These results led to diagnosis of a new genetic disorder for 1 (12.5%) patient and screening recommendations for 2 (25%) patients. An RNF213 variant in one patient led to recommendations for family member screening and pulmonary hypertension screening. Another patient was diagnosed with CBL disorder and referred for cancer screening. The median age at surgery in patients with clinically actionable findings was 4.6 years compared to 9.2 years in those who were referred for genetic testing. All 3 patients who had an actionable finding had developmental delay. CONCLUSION: It may be beneficial to refer moyamoya patients under 5 for genetic screening given the high likelihood of discovering actionable mutations.

Posterior cerebral territory ischemia in pediatric moyamoya: Surgical techniques and long-term clinical and radiographic outcomes.

PURPOSE: To describe a surgical technique for posterior cerebral revascularization in pediatric patients with moyamoya arteriopathy. Here, we describe the clinical characteristics, surgical indications, operative techniques, and clinical and radiographic outcomes in a series of pediatric patients with moyamoya disease affecting the posterior cerebral artery (PCA) territory. METHODS: A retrospective single-center series of all pediatric patients with moyamoya disease who presented to our institute between July 2009 through August 2019 were reviewed. The clinical characteristics, surgical indications, operative techniques, and long-term clinical and radiographic outcomes of pediatric moyamoya patients with PCA territory ischemia were collected and analyzed. RESULTS: A total of 10 PCA revascularization procedures were performed in 9 patients, 5 female, ages 1 to 11.1 years (average 5.2 years). Complications included 1 stroke, with no infections, hemorrhages, seizures, or deaths. One patient had less than 1 year of radiographic and clinical follow-up. In 8 of 9 patients with at least 1 year of radiographic follow-up, there was engraftment of surgical vessels present in all cases. No new strokes were identified on long-term follow-up despite the radiographic progression of the disease. In the 8 cases available for analysis, the average follow-up was 50.8 months with a range of 12 to 117 months. CONCLUSIONS: PCA territory ischemia in patients with progressive moyamoya disease can be surgically treated with indirect revascularization. Here, we describe our experience with PCA revascularization procedures for moyamoya disease, including pial pericranial dural (PiPeD) revascularization and pial synangiosis utilizing the occipital artery. These surgical options may be useful for decreasing the risk of stroke in pediatric moyamoya patients with severe posterior circulation disease.

Evolution of clinical and translational advances in the management of pediatric arteriovenous malformations.

Arteriovenous malformations (AVMs) represent one of the most challenging diagnoses in pediatric neurosurgery. Until recently, the majority of AVMs was only identified after hemorrhage and primarily treated with surgery. However, recent advances in a wide range of fields-imaging, surgery, interventional radiology, radiation therapy, and molecular biology-have profoundly advanced the understanding and therapy of these complex lesions. Here we review the progress made in pediatric AVMs with a specific focus on innovations relevant to clinical care.

Surgical considerations for spinal epidural hematoma evacuation in the setting of blue rubber bleb nevus syndrome in a child.

Blue rubber bleb nevus syndrome (BRBNS) is a rare condition that presents with venous malformation blebs throughout the body, most commonly on the skin and gastrointestinal tract. There have only been a limited number of reports of benign BRBNS lesions involving the spine in children, which were detected after chronic symptomatology. We herein present a unique case of a ruptured BRBNS venous malformation into the epidural space of the lumbar spine in a child presenting with acute neurologic deficit and discuss the relevant surgical considerations for operating in the setting of BRBNS.

The composition of landmark vein of Galen malformation research: the emergence of endovascular treatments.

BACKGROUND: Since the advent of endovascular treatment, the long-term prognosis of vein of Galen malformation (VOGM) has markedly improved; however, the nature of research leading to this point is unclear. The objective of this study was to define the composition of VOGM research to date, by means of a bibliometric analysis of the 100 most cited VOGM articles. METHODS: An electronic search of Elsevier's Scopus database was performed to identify the 100 most cited articles on VOGM screened against predetermined criteria. Data were then compared. RESULTS: The 100 most cited VOGM articles were published between 1974 and 2017 in 38 unique journals and originated from 16 unique countries. Mean citation count and rate were 59.4 citations and 2.9 citations/year, respectively. The USA (n = 42); Hôpital de Bicêtre, France (n = 15); and Dr. Pierre Lasjaunias (n = 16) were the largest individual country, institutional, and author contributors. Compared to the older articles (published < 2000), key differences for newer articles were statistically higher citation rates (P < 0.01), more authors (P < 0.01), higher proportion of endovascular treatment descriptions (P = 0.01), and more originating from Asia Pacific (P < 0.01). CONCLUSIONS: From the 100 most cited VOGM articles to date, there has been a noticeable shift from diagnosing VOGM based on the foundational work by Dr. Lasjaunias to understanding how we can model clinical outcomes now that endovascular treatment has become the standard of care. Significant shifts in prognosis are pending, and the current bibliometric data implicate we are on the precipice of more recent works making an impact in the near future.

Intracranial venous malformation masquerading as a meningioma in PI3KCA-related overgrowth spectrum disorder.

Gain of function PIK3CA pathogenic variants have been identified in overgrowth syndromes collectively termed "PIK3CA-related overgrowth spectrum" (PROS). There are no previously reported cases of cerebrovascular venous malformations in PROS syndromes, though somatic activating PIK3CA variants have been identified in extracranial venous malformation. This study was approved by the Institutional Review Boar at Boston Children's Hospital. A 14-year-old female mosaic for the de novo p.R108H pathogenic variant in the PIK3CA gene was found to have a large tumor involving the superior sagittal sinus with mass effect on the motor cortex most consistent with a parafalcine meningioma. She underwent surgical resection with pathology demonstrating a venous malformation. PIK3CA pathogenic variants have been identified in nonsyndromic extracranial venous and lymphatic malformations as well in brain tumors, including glioma and meningioma. However, PIK3CA variants have not previously been identified in purely intracranial venous malformations. This distinction is relevant to treatment decisions, given that mTOR inhibitors may provide an alternative option for noninvasive therapy in cases of suspected venous malformation.

Two Sides of a Coin: Case Report of Unilateral Synangiosis and Contralateral Stroke Highlighting Consequences of Disease Progression and Efficacy of Revascularization in Sickle Cell Disease-Associated Moyamoya Syndrome.

Moyamoya syndrome increases the risk of stroke in sickle cell disease, but revascularization surgery can modify this risk. Collaborative management between hematology and neurosurgery offers effective strategies to reduce stroke risk in these patients. We describe a challenging case where a patient with sickle cell disease undergoing standard of care management as prescribed by the Stroke Prevention Trial in Sickle Cell Anemia and revascularization with pial synangiosis subsequently developed rapidly progressive disease in other cerebral vessels and suffered ischemic hemispheric stroke. This case not only demonstrates the success of management in accordance with the American Heart Association (AHA) and American Stroke Association (ASA) guidelines but also demonstrates critical areas where we lack understanding of disease progression.

Complete Neurological Recovery After Emergency Burr Hole Placement Utilizing EZ-IO® for Epidural Hematoma.

BACKGROUND: Post-traumatic epidural hematoma (EDH) accounts for 1-3% of pediatric closed head injury admissions. There is a 2.5:1 male predominance. Etiology varies by age; motor vehicle collisions are the primary cause of EDH in adolescents. Post-traumatic EDH accompanies up to 4% of adult head injuries, and is associated with 10% mortality in adults and 5% mortality in children. In North America, standard of care for post-traumatic EDH includes decompressive craniotomy or trepanation via burr hole. Such lifesaving care is typically provided in the operating room by consulting neurosurgery teams or other personnel trained in the use of burr hole equipment. CASE REPORT: The case of a 17-year-old female patient who presented to a community emergency department (ED) after being involved in a motor vehicle collision is discussed. At the scene of the accident, she refused emergency medical services transport and was brought to the ED via private vehicle. She quickly decompensated in the ED and required intubation. Neurosurgical services were not available and transport to the nearest pediatric trauma center was delayed due to weather. Decompression and drainage of her EDH was accomplished with an EZ-IO® driver and intraosseous needle under virtual guidance of a pediatric neurosurgeon until definitive care could be obtained. The patient made a full neurologic recovery. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS: EDHs have high morbidity and mortality. In settings without access to neurosurgical services, and where ED access to or familiarity with burr hole equipment is limited, the EZ-IO® device may be a temporizing and lifesaving intervention until definitive neurosurgical care can be obtained.

External carotid artery to internal carotid artery transposition to augment flow for a superficial temporal artery to middle cerebral artery bypass associated with severe external carotid artery stenosis.

BACKGROUND: Donor vessel quality can impact the outcome of extracranial-intracranial (EC-IC) bypass. External carotid artery (ECA) disease may produce embolism into the anastomosis and cerebral territory and possibly reduce flow in the superficial temporal artery (STA). Previously reported remedies to ECA stenosis include ECA endarterectomy, stenting, and angioplasty. Clinical presentation A middle-aged patient with chronic left MCA occlusion, progressive ischemic symptoms on maximal medical therapy, and imaging confirmation of compromised hemodynamic reserve was evaluated for EC-IC bypass. Angiography demonstrated severe ECA origin stenosis. An ECA-ICA transposition was performed, primarily to eliminate the risk of emboli and secondarily to possibly improve the STA flow. The patient sustained an excellent radiological and clinical outcome, and the STA donor cut-flow was increased modestly by 22% (45 to 55 mL/min). CONCLUSION: This case is the first report of an ECA to internal carotid artery transposition as an option in the management of ECA stenosis in preparation for an STA-MCA bypass for the purpose of flow augmentation.

Natural History of Hemodynamics in Vertebrobasilar Disease: Temporal Changes in the VERiTAS Study Cohort.

BACKGROUND AND PURPOSE: The role of regional hypoperfusion as a contributor to stroke risk in atherosclerotic vertebrobasilar disease has recently been confirmed by the observational VERiTAS (Vertebrobasilar Flow Evaluation and Risk of Transient Ischemic Attack and Stroke) Study. We examined the stability of hemodynamic status over time and its relationship to stroke risk in patients from this prospective cohort. METHODS: VERiTAS enrolled patients with recently symptomatic ≥50% atherosclerotic stenosis/occlusion of vertebral and/or basilar arteries. Large vessel flow in the vertebrobasilar territory was assessed using quantitative magnetic resonance angiography, and patients were designated as low or normal flow based on distal territory regional flow, incorporating collateral capacity. Patients underwent standard medical management and follow-up for primary outcome event of vertebrobasilar territory stroke. Quantitative magnetic resonance angiography imaging was repeated at 6, 12, and 24 months. Flow status over time was examined relative to baseline and relative to subsequent stroke risk using a cause-specific proportional hazard model, with flow status treated as a time-varying covariate. Mean blood pressure was examined to assess for association with changes in flow status. RESULTS: Over 19±8 months of follow-up, 132 follow-up quantitative magnetic resonance angiography studies were performed in 58 of the 72 enrolled patients. Of the 13 patients with serial imaging who had low flow at baseline, 7 (54%) had improvement to normal flow at the last follow-up. Of the 45 patients who had normal flow at baseline, 3 (7%) converted to low flow at the last follow-up. The mean blood pressure did not differ in patients with or without changes in flow status. The time-varying flow status remained a strong predictor of subsequent stroke (hazard ratio, 10.3 [95% CI, 2.2-48.7]). CONCLUSIONS: There is potential both for improvement and worsening of hemodynamics in patients with atherosclerotic vertebrobasilar disease. Flow status, both at baseline and over time, is a risk factor for subsequent stroke, thus serving as an important prognostic marker. Registration: URL: https://clinicaltrials.gov. Unique identifier: NCT00590980.

Genome-wide investigation of intragenic DNA methylation identifies ZMIZ1 gene as a prognostic marker in glioblastoma and multiple cancer types.

DNA methylation has long been recognized as a tumor-promoting factor when aberrantly regulated in the promoter region of genes. However, the effect of intragenic DNA methylation remains poorly understood on the clinical aspects of cancer. Here, we first evaluated the significance of intragenic DNA methylation for survival outcomes of cancer patients in a genome-wide manner. Glioblastoma patients with hypermethylated intragenic regions exhibited better survival than hypomethylated patients. Enrichment analyses of intragenic DNA methylation profiles with epigenetic signatures prioritized the intragenic DNA methylation of ZMIZ1 as a possible glioblastoma prognostic marker that is independent of MGMT methylation in IDH1 wild-type patients. This intragenic region harbored molecular signatures of alternative transcription across many cell types. Furthermore, we found that the intragenic region of ZMIZ1 can serve as a molecular marker in multiple cancers including astrocytomas, bladder cancer and renal cell carcinoma according to DNA methylation status. Finally, in vitro and in vivo experiments uncovered the role of ZMIZ1 as a driver of tumor cell migration. Altogether, our results identify ZMIZ1 as a prognostic marker in cancer and highlight the clinical significance of intragenic methylation in cancer.

A coil in the hair-a case report of percutaneous coil migration.

Coil migration following cerebral aneurysm treatment has been described and may result in stroke, recurrent aneurysm, or local mass effect. Cerebral coil embolization is also applied in arteriovenous malformations and arteriovenous fistulas, but these pathologies are relatively rare and coil migration is not as well described. Furthermore, these cases are more commonly treated with combinations of multiple modalities to achieve cure. Embolization, surgery, and radiation each have risks and benefits and combinations may have synergistic risks and benefits not seen in monotherapy. We report a case of extravascular and extra-corporeal coil migration after embolization and craniectomy to treat a patient with hemorrhage from an arteriovenous fistula.

Vision outcomes in patients with paraclinoid aneurysms treated with clipping, coiling, or flow diversion: a systematic review and meta-analysis.

OBJECTIVE Patients with paraclinoid aneurysms commonly present with visual impairment. They have traditionally been treated with clipping or coiling, but flow diversion (FD) has recently been introduced as an alternative treatment modality. Although there is still initial aneurysm thrombosis, FD is hypothesized to reduce mass effect, which may decompress the optic nerve when treating patients with visually symptomatic paraclinoid aneurysms. The authors performed a meta-analysis to compare vision outcomes following clipping, coiling, or FD of paraclinoid aneurysms in patients who presented with visual impairment. METHODS A systematic literature review was performed using the PubMed and Web of Science databases. Studies published in English between 1980 and 2016 were included if they reported preoperative and postoperative visual function in at least 5 patients with visually symptomatic paraclinoid aneurysms (cavernous segment through ophthalmic segment) treated with clipping, coiling, or FD. Neuroophthalmological assessment was used when reported, but subjective patient reports or objective visual examination findings were also acceptable. RESULTS Thirty-nine studies that included a total of 2458 patients (520 of whom presented with visual symptoms) met the inclusion criteria, including 307 visually symptomatic cases treated with clipping (mean follow-up 26 months), 149 treated with coiling (mean follow-up 17 months), and 64 treated with FD (mean follow-up 11 months). Postoperative vision in these patients was classified as improved, unchanged, or worsened compared with preoperative vision. A pooled analysis showed preoperative visual symptoms in 38% (95% CI 28%-50%) of patients with paraclinoid aneurysms. The authors found that vision improved in 58% (95% CI 48%-68%) of patients after clipping, 49% (95% CI 38%-59%) after coiling, and 71% (95% CI 55%-84%) after FD. Vision worsened in 11% (95% CI 7%-17%) of patients after clipping, 9% (95% CI 2%-18%) after coiling, and 5% (95% CI 0%-20%) after FD. New visual deficits were found in patients with intact baseline vision at a rate of 1% (95% CI 0%-3%) for clipping, 0% (95% CI 0%-2%) for coiling, and 0% (95% CI 0%-2%) for FD. CONCLUSIONS To the authors' knowledge, this is the first meta-analysis to assess vision outcomes after treatment for paraclinoid aneurysms. The authors found that 38% of patients with these aneurysms presented with visual impairment. These data also demonstrated a high rate of visual improvement after FD without a significant difference in the rate of worsened vision or iatrogenic visual impairment compared with clipping and coiling. These findings suggest that FD is an effective option for treatment of visually symptomatic paraclinoid aneurysms.

Motor cortex arteriovenous malformation.

Supratentorial arteriovenous malformations in eloquent territories can be difficult to resect. This video presents the treatment of a patient with a symptomatic 3-cm arteriovenous malformation in the left motor strip. At the authors' institution, per the surgeon's discretion, preoperative angiography is performed to evaluate the need for preoperative embolization. Multimodality treatment reduced the microsurgical risk by allowing early occlusion of a draining vein, by decreasing overall intraoperative hemorrhage, and by allowing minimal pial dissection in the deep aspect of the arteriovenous malformation that abutted the corticospinal tract. The choice of embolysate was an additional nuance of the embolization. The video can be found here: https://youtu.be/HWZ0RjgPEXg .

Considerations in Applying a New Stent Retriever in Pediatric Endovascular Cerebral Thrombectomy for Acute Ischemic Stroke.

Acute ischemic stroke (AIS) in children has been difficult to diagnose, treat and study, due to atypical clinical presentation, imaging challenges and the rarity of large-vessel embolic occlusion as the etiology of acute neurological change in children. With endovascular thrombectomy showing success in randomized trials of adult AIS, the technique is increasingly being extrapolated to pediatric stroke. However, there is little evidence regarding the safety or efficacy of applying in children these devices developed and tested in adults. There is concern about a vessel-to-device size mismatch that may result in a different complication and benefit profile than typically seen. We report on the successful application in pediatric stroke of a newer-generation, smaller stent retriever, designed to be delivered through relatively smaller and more navigable microcatheters than the prior generation of this device.

The role of regulatory T cells and microglia in glioblastoma-associated immunosuppression.

Cell-mediated suppression of anti-tumor immunity is multifactorial in patients with cancer, and recent studies have focused on several distinct cellular agents that are associated with this phenomenon. This review will focus on the potential role of regulatory T cells (Tregs) and microglia in the suppression of cellular immunity observed in patients with glioblastoma. We discuss the ontogeny, basic biology, evidence for activity, and potential clinical options for targeting Tregs and microglia as part of immunotherapy in affected patients.