Moyamoya disease/cerebral vasculopathy in osteopathia striata with cranial sclerosis: a rare but important complication.

Osteopathia striata with cranial sclerosis (OSCS) is a rare X-linked dominant sclerosing osteodysplasia, due to AMER1 pathogenic variants. Characteristic features include craniofacial sclerosis and long-bone metaphyseal striations. Moyamoya disease (a type of progressive cerebral vasculopathy) and other types of cerebral vascular disease are not currently clearly associated with OSCS (except for two separate case reports), and can often first present with stroke. Through informal networks with UK-based bone experts and the UK skeletal dysplasia group, three cases from the UK and Ireland were identified. Medical literature was also reviewed to identify the known cases of OSCS with the described complications. We report four females, in whom OSCS and cerebral vasculopathy co-exist, with varying clinical outcomes. There appears to be an emerging association between OSCS and cerebral vasculopathy, which pre-disposes patients to stroke. Given this, screening OSCS patients for cerebral vasculopathy may be of value, especially pre-surgery. Further research regarding optimal screening and management is needed. The mechanism of cerebral vasculopathy and its progression remain unclear.

Feasibility of comparing medical management and surgery (with neurosurgery or stereotactic radiosurgery) with medical management alone in people with symptomatic brain cavernoma - protocol for the Cavernomas: A Randomised Effectiveness (CARE) pilot trial.

INTRODUCTION: The top research priority for cavernoma, identified by a James Lind Alliance Priority setting partnership was 'Does treatment (with neurosurgery or stereotactic radiosurgery) or no treatment improve outcome for people diagnosed with a cavernoma?' This pilot randomised controlled trial (RCT) aims to determine the feasibility of answering this question in a main phase RCT. METHODS AND ANALYSIS: We will perform a pilot phase, parallel group, pragmatic RCT involving approximately 60 children or adults with mental capacity, resident in the UK or Ireland, with an unresected symptomatic brain cavernoma. Participants will be randomised by web-based randomisation 1:1 to treatment with medical management and with surgery (neurosurgery or stereotactic radiosurgery) versus medical management alone, stratified by prerandomisation preference for type of surgery. In addition to 13 feasibility outcomes, the primary clinical outcome is symptomatic intracranial haemorrhage or new persistent/progressive focal neurological deficit measured at 6 monthly intervals. An integrated QuinteT Recruitment Intervention (QRI) evaluates screening logs, audio recordings of recruitment discussions, and interviews with recruiters and patients/parents/carers to identify and address barriers to participation. A Patient Advisory Group has codesigned the study and will oversee its progress. ETHICS AND DISSEMINATION: This study was approved by the Yorkshire and The Humber-Leeds East Research Ethics Committee (21/YH/0046). We will submit manuscripts to peer-reviewed journals, describing the findings of the QRI and the Cavernomas: A Randomised Evaluation (CARE) pilot trial. We will present at national specialty meetings. We will disseminate a plain English summary of the findings of the CARE pilot trial to participants and public audiences with input from, and acknowledgement of, the Patient Advisory Group. TRIAL REGISTRATION NUMBER: ISRCTN41647111.

Surgical revascularizations for pediatric moyamoya: a systematic review, meta-analysis, and meta-regression analysis.

INTRODUCTION: There is no clear consensus regarding the technique of surgical revascularization for moyamoya disease and syndrome (MMD/MMS) in the pediatric population. Previous meta-analyses have attempted to address this gap in literature but with methodological limitations that affect the reliability of their pooled estimates. This meta-analysis aimed to report an accurate and transparent comparison between studies of indirect (IB), direct (DB), and combined bypasses (CB) in pediatric patients with MMD/MMS. METHODS: In accordance with PRISMA guidelines, systematic searches of Medline, Embase, and Cochrane Central were undertaken from database inception to 7 October 2022. Perioperative adverse events were the primary outcome measure. Secondary outcomes were rates of long-term revascularization, stroke recurrence, morbidity, and mortality. RESULTS: Thirty-seven studies reporting 2460 patients and 4432 hemispheres were included in the meta-analysis. The overall pooled mean age was 8.6 years (95% CI: 7.7; 9.5), and 45.0% were male. Pooled proportions of perioperative adverse events were similar between the DB/CB and IB groups except for wound complication which was higher in the former group (RR = 2.54 (95% CI: 1.82; 3.55)). Proportions of post-surgical Matsushima Grade A/B revascularization favored DB/CB over IB (RR = 1.12 (95% CI 1.02; 1.24)). There was no significant difference in stroke recurrence, morbidity, and mortality. After meta-regression analysis, year of publication and age were significant predictors of outcomes. CONCLUSIONS: IB, DB/CB are relatively effective and safe revascularization options for pediatric MMD/MMS. Low-quality GRADE evidence suggests that DB/CB was associated with better long-term angiographic revascularization outcomes when compared with IB, although this did not translate to long-term stroke and mortality benefits.

Neurosurgical management of proton beam therapy-induced moyamoya syndrome.

OBJECTIVE: Proton beam therapy (PBT) is an increasingly used treatment modality for pediatric patients with brain tumors. Moyamoya syndrome (MMS) is well recognized as a complication of traditional photon radiotherapy, however its association with PBT is less well described. The authors discuss their initial experience with the neurosurgical management of MMS secondary to PBT in a large-volume pediatric neurovascular service. METHODS: The authors performed a retrospective case review of consecutive children referred for neurosurgical management of MMS after PBT between 2009 and 2022. Patient demographic characteristics, oncological history and treatment, interval between PBT and MMS diagnosis, and MMS management were recorded. Clinical outcome at last review was classified as good if the modified Rankin Scale (mRS) score was ≤ 2 and/or the patient attended mainstream education without additional assistance. Poor outcome was defined as mRS score ≥ 3 and/or the patient received additional educational support. The recorded radiological outcomes included angiographic analysis of stenosis, evidence of brain ischemia/infarction on MRI, and postsurgical angiographic revascularization. RESULTS: Ten patients were identified. Oncological diagnosis included craniopharyngioma (n = 6), optic pathway glioma (1), ependymoma (1), Ewing sarcoma (1), and rhabdosarcoma (1). The median (interquartile range [IQR]) age at PBT was 5.1 (2.7-7.9) years. The median (IQR) age at MMS diagnosis was 7.8 (5.7-9.3) years. The median time between PBT and diagnosis of MMS was 20 (15-41) months. Six patients had poor functional status after initial oncological treatment and prior to diagnosis of MMS. All 10 patients had endocrine dysfunction, 8 had visual impairment, and 4 had behavioral issues prior to MMS diagnosis. Four patients had a perioperative ischemic event: 2 after tumor surgery, 1 after MMS surgical revascularization, and 1 after receiving a general anesthetic for an MRI scan during oncological surveillance. Seven children were treated with surgical revascularization, whereas 3 were managed medically. The incidence of ischemic events per cerebral hemisphere was reduced after surgical revascularization: only 1 patient of 7 had an ischemic event during the follow-up period after surgery. No children moved from good to poor functional status after MMS diagnosis. CONCLUSIONS: MMS can occur after PBT. Magnetic resonance angiography sequences should be included in surveillance MRI scans to screen for MMS, and families should be counseled about this complication. Management at a high-volume pediatric neurovascular center, including selective use of revascularization surgery, appears to maintain functional status in these children.

Surgical revascularization for pediatric moyamoya: the role of surgical mentorship in sustaining and developing a neurovascular service.

OBJECTIVE: Obtaining operative experience for the treatment of rare conditions in children represents a challenge for pediatric neurosurgeons. Starting in November 2017, a surgeon was mentored in surgical revascularization (SR) for pediatric moyamoya with a view to service development and sustainability. The aim of this audit was to evaluate early outcomes of SR for pediatric moyamoya during and following a surgical mentorship. METHODS: A retrospective cohort study with chart/database review of consecutive moyamoya surgeries performed by a new attending surgeon (between November 2017 and March 2020) was compared to a previously published cohort from the authors' institution in terms of clinical and angiographic outcomes, complications, operating time, and length of stay. A standardized technique of encephaloduroarteriomyosynangiosis with the superficial temporal artery was used. RESULTS: Twenty-two children underwent 36 indirect SRs during the study period. Patient demographics were similar between cohorts. The first group of 6 patients had 11 SRs performed jointly by the new attending surgeon mentored by an established senior surgeon (group A), followed by 10 patients with 16 SRs performed independently by the new attending surgeon (group B). The last 6 patients had 9 SRs with the new attending surgeon mentoring a senior fellow (group C) in performing SR. Good angiographic collateralization (Matsushima grades A and B) was observed in 80% of patients, with similar proportions across all 3 groups. A total of 18/19 symptomatic patients (95%) derived symptomatic benefit. There was no perioperative death and, compared to the historical cohort, a similar proportion had a recurrent arterial ischemic event (i.e., acute ischemic stroke) necessitating a second SR (1/22 vs 3/73). Operative times were longest in group C, with no difference in length of hospital stay among the 3 groups. CONCLUSIONS: Early outcomes demonstrate the feasibility of mentorship for safely incorporating new neurosurgeons in sustaining and developing a tertiary-level surgical service.

Predictors of motor outcome after childhood arterial ischemic stroke.

AIM: To identify clinical and radiological predictors of long-term motor outcome after childhood-onset arterial ischemic stroke (AIS) in the middle cerebral artery (MCA) territory. METHOD: Medical records of 69 children (36 females, 33 males; median age at index AIS 3y 3mo, range: 1mo-16y) who presented to Great Ormond Street Hospital with first AIS in the MCA territory were reviewed retrospectively. Cases were categorized using the Childhood AIS Standardized Classification and Diagnostic Evaluation (CASCADE). Magnetic resonance imaging (MRI) and angiography were evaluated. An Alberta Stroke Program Early Computed Tomography Score (ASPECTS) was calculated on MRI. The Recurrence and Recovery Questionnaire assessed motor outcome and was dichotomized into good/poor. RESULTS: Eventual motor outcome was good in 49 children and poor in 20. There were no acute radiological predictors of eventual motor outcome. At follow-up, CASCADE 3A (i.e. moyamoya) and Wallerian degeneration were significantly associated with poor motor outcome. In the multivariate analysis, younger age and CASCADE 3A predicted poor motor outcome. INTERPRETATION: In the context of recommendations regarding unproven and potentially high-risk hyperacute therapies for childhood AIS, prediction of outcome could usefully contribute to risk/benefit analysis. Unfortunately, paradigms used in adults, such as ASPECTS, are not useful in children in the acute/early subacute phase of AIS. What this paper adds Adult paradigms, such as the Alberta Stroke Program Early Computed Tomography Score system, are not useful for predicting outcome in children. Younger children tend to have a poorer long-term prognosis than older children. Moyamoya is associated with poor prognosis.

Management of haemorrhagic stroke secondary to arteriovenous malformations in childhood.

AIMS: The aim of this study is to describe the outcome and management of all children who have presented with haemorrhagic stroke (HS) secondary to an arteriovenous malformation (AVM) at a single UK centre over a 13-year period. METHODS: All children with HS managed at our institution (2005-2018) were identified and those with underlying AVMs were studied. Clinical and imaging data were obtained from medical records. Outcome was scored using the Recovery and Recurrence Questionnaire. RESULTS: Ninety-three children (median age 8.8 years; 56 males; 8 neonates) presented with both global and focal features (28 had Glasgow Coma Score < 8). Haemorrhage was intraparenchymal in 72; prior risk factors present in 14. An underlying vascular lesion was identified in 68/93, most commonly AVM (n = 48). A systemic cause was found in 10, cerebral venous thrombosis in three, and 9 remain unidentified despite neuroradiological investigation. Median follow-up was 2.4 years, six died, and one was lost to follow-up. Outcome was rated as good in 60/86. Of the 48 AVMs, 3 were Spetzler-Martin (SM) grade 1, 21 SM 2, 21 SM3 and 3 SM4. One patient was treated conservatively as the AVM was too high risk to treat. At follow-up, 19 with AVM were angiographically cured, all with low SM grade and with the use of a single modality in 9 cases (all low SM grade). CONCLUSION: Although children with acute HS are extremely unwell at presentation, supportive care results in a good outcome in the majority. Complete obliteration for childhood AVMs is challenging even with low-grade lesions with multimodal treatment.

Cerebral arteriopathy associated with heterozygous variants in the casitas B-lineage lymphoma gene.

OBJECTIVE: To report a series of patients with cerebral arteriopathy associated with heterozygous variants in the casitas B-lineage lymphoma (CBL) gene and examine the functional role of the identified mutant Cbl protein. We hypothesized that mutated Cbl fails to act as a negative regulator of the RAS-mitogen-activated protein kinases (MAPK) signaling pathway, resulting in enhanced vascular fibroblast proliferation and migration and enhanced angiogenesis and collateral vessel formation. METHODS: We performed whole-exome sequencing in 11 separate families referred to Great Ormond Street Hospital, London, with suspected genetic cause for clinical presentation with severe progressive cerebral arteriopathy. RESULTS: We identified heterozygous variants in the CBL gene in 5 affected cases from 3 families. We show that impaired CBL-mediated degradation of cell surface tyrosine kinase receptors and dysregulated intracellular signaling through the RAS-MAPK pathway contribute to the pathogenesis of the observed arteriopathy. Mutated CBL failed to control the angiogenic signal relay of vascular endothelial growth factor receptor 2, leading to prolonged tyrosine kinase signaling, thus driving angiogenesis and collateral vessel formation. Mutant Cbl promoted myofibroblast migration and proliferation contributing to vascular occlusive disease; these effects were abrogated following treatment with a RAF-RAS-MAPK pathway inhibitor. CONCLUSIONS: We provide a possible mechanism for the arteriopathy associated with heterozygous CBL variants. Identification of the key role for the RAS-MAPK pathway in CBL-mediated cerebral arteriopathy could facilitate identification of novel or repurposed druggable targets for treating these patients and may also provide therapeutic clues for other cerebral arteriopathies.

Microparticle-mediated VZV propagation and endothelial activation: Mechanism of VZV vasculopathy.

OBJECTIVE: Varicella zoster virus (VZV) can spread anterogradely and infect cerebral arteries causing VZV vasculopathy and arterial ischemic stroke. In this study, we tested the hypothesis that virus-infected cerebrovascular fibroblasts undergo phenotypic changes that promote vascular remodeling and facilitate virus transmission in an in vitro model of VZV vasculopathy. The aims of this project were therefore to examine the changes that virus-infected human brain adventitial vascular fibroblasts (HBVAFs) undergo in an in vitro model of VZV vasculopathy and to identify disease biomarkers relating to VZV-related vasculopathy. METHODS: HBVAFs were infected with VZV, and their ability to migrate, proliferate, transdifferentiate, and interact with endothelial cells was studied with flow cytometry. Microparticles (MPs) released from these cells were isolated and imaged with transmission electron microscopy, and their protein content was analyzed with mass spectrometry. Circulating MP profiles were also studied in children with VZV and non-VZV vasculopathy and compared with controls. RESULTS: VZV-infected HBVAFs transdifferentiated into myofibroblasts with enhanced proliferative and migratory capacity. Interaction of VZV-infected HBVAFs with endothelial cells resulted in endothelial dysfunction. These effects were, in part, mediated by the release of MPs from VZV-infected HBVAFs. These MPs contained VZV virions that could transmit VZV to neighboring cells, highlighting a novel model of VZV cell-to-cell viral dissemination. MPs positive for VZV were significantly higher in children with VZV-related vasculopathy compared to children with non-VZV vasculopathy (p = 0.01) and controls (p = 0.007). CONCLUSIONS: VZV-infected HBVAFs promote vascular remodeling and facilitate virus transmission. These effects were mediated by the release of apoptotic MPs that could transmit VZV infection to neighboring cells through a Trojan horse means of productive viral infection. VZV+ MPs may represent a disease biomarker worthy of further study.

Intracranial vascular pathology in two further patients with Floating-Harbor syndrome: Proposals for cerebrovascular disease risk management.

Floating-Harbor syndrome (FHS) is a rare, heritable disorder caused by variants in the SRCAP gene. Most individuals with FHS have characteristic facial features, short stature, and speech and language impairment. Although FHS has been likely under-diagnosed due to a combination of lack of recognition of the clinical phenotype and limited access to genomic testing, it is a rare condition with around 100 individuals reported in the medical literature. Case series have been biased towards younger individuals (vast majority <20 years of age) meaning that it has been challenging to provide accurate medical advice for affected individuals in adulthood. We report two young adults with FHS who presented with intracranial haemorrhage likely secondary to cerebrovascular aneurysms, with devastating consequences, making a total of four FHS patients reported with significant cerebrovascular abnormalities. Three of four patients had hypertension, at least one in conjunction with normal renal structure. We consider possible relationships between hypertension, renal pathology and aneurysms in the context of FHS, and consider mechanisms through which disruption of the SRCAP protein may lead to vascular pathology. We recommend that clinicians should have a low threshold to investigate symptoms suggestive of cerebrovascular disease in FHS. We advise that patients with FHS should have annual blood pressure monitoring from adolescence, renal ultrasound at diagnosis repeated in adulthood, and timely investigation of any neurological symptoms. For patients with FHS, particularly with hypertension, we advise that clinicians should consider at least one MRA (Magnetic Resonance Imaging with Angiography) to check for cerebral aneurysms.

Novel missense variants in the RNF213 gene from a European family with Moyamoya disease.

In this report, we present a European family with six individuals affected with Moyamoya disease (MMD). We detected two novel missense variants in the Moyamoya susceptibility gene RNF213, c.12553A>G (p.(Lys4185Glu)) and c.12562G>A (p.(Ala4188Thr)). Cosegregation of the variants with MMD, as well as a previous report of a variant affecting the same amino acid residue in unrelated MMD patients, supports the role of RNF213 in the pathogenesis of MMD.

Seeking normality: Parents' experiences of childhood stroke.

BACKGROUND: Incidence of paediatric stroke has been estimated to range from 1.2 to 13 per 100,000 children under 18 years of age. It is a significant cause of long-term morbidity in children with long-term impacts on physical, cognitive, psychological, and social outcomes. However, little is known about the experiences of parents caring for a child with stroke. Such information is needed to inform the development of child- and family-centred care. METHODS: We conducted in-depth interviews with parents of children with stroke. Participants were purposively sampled from three regional specialist services in England, based on the age of the child at stroke onset and time since first stroke. Interviews used a topic guide and were audio recorded and transcribed in full. Thematic analysis was conducted to develop an account that reflected patients' experiences from their own perspectives. RESULTS: Twelve parents participated with five children classified as having no to mild deficits and seven with moderate to severe deficits. Parents were concerned about the effects of stroke on the child's psychological, cognitive, and social well-being. Significant impacts on parents own well-being and on the family were reported. Although most experienced good quality acute care, meeting the child's needs after hospital discharge was problematic, with low levels of awareness of paediatric stroke among professionals and difficulties accessing relevant information and services. Meeting special education needs was variable. Parents were proactive in seeking to establish a sense of normality for the child and themselves. CONCLUSIONS: The findings illuminate a wider picture of paediatric stroke than indicated by clinical outcomes alone. Parents' experiences varied according to the child's needs but also family's situation and geographical location. Particular attention should be paid to co-ordinating services to meet multiple needs after discharge from hospital.

Quantifying the Intra-Operative Hemodynamic Effects of Glue Embolization in Vein of Galen Malformations.

Vein of Galen malformation is a rare congenital pathological intracranial arteriovenous shunt which carries 30% risk of death before 28 days-of-age. Treatment is by high risk minimally invasive endovascular glue embolization of shunt feeding arteries under angiographic control. A tool to support intra-operative decision making would be useful. We present a novel method for visualizing angiography data to demonstrate the effect of the intervention based upon change the after embolization in the delay in time of peak contrast density relative to the injected artery and a novel method for quantifying the immediate effect of embolization on the hemodynamics of the shunt. The method is demonstrated on the angiograms of five neonates who underwent embolization. We show consistent results including a post-embolization increase in the delay in time of peak contrast density relative to the injected artery at the venous outflow in keeping with reduced shunting and redistribution of blood following embolization.

Cross-sectional study of a United Kingdom cohort of neonatal vein of galen malformation.

OBJECTIVE: Describe the course and outcomes in a UK national cohort of neonates with vein of Galen malformation identified before 28 days of life. METHODS: Neonates with angiographically confirmed vein of Galen malformation presenting to 1 of 2 UK treatment centers (2006-2016) were included; those surviving were invited to participate in neurocognitive assessment. Results in each domain were dichotomized into "good" and "poor" categories. Cross-sectional and angiographic brain imaging studies were systematically interrogated. Logistic regression was used to explore potential outcome predictors. RESULTS: Of 85 children with neonatal vein of Galen malformation, 51 had survived. Thirty-four participated in neurocognitive assessment. Outcomes were approximately evenly split between "good" and "poor" categories across all domains, namely, neurological status, general cognition, neuromotor skills, adaptive behavior, and emotional and behavioral development. Important predictors of poor cognitive outcome were initial Bicêtre score ≤ 12 and presence of brain injury, specifically white matter injury, on initial imaging; in multivariate analysis, only Bicêtre score ≤ 12 remained significant. INTERPRETATION: Despite modern supportive and endovascular treatment, more than one-third of unselected newborns with vein of Galen malformation did not survive. Outcome was good in around half of survivors. The importance of white matter injury suggests that abnormalities of venous as well as arterial circulation are important in the pathophysiology of brain injury. Ann Neurol 2018;84:547-555.