Surgical Revascularization as a Procedure to Prevent Neurological Complications in children with Moyamoya Syndrome Associated with Neurofibromatosis I: a Single Institution Case Series

Surgical Revascularization as a Procedure to Prevent Neurological Complications in children with Moyamoya Syndrome Associated with Neurofibromatosis I: a Single Institution Case Series | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Surgical Revascularization as a Procedure to Prevent Neurological Complications in children with Moyamoya Syndrome Associated with Neurofibromatosis I: a Single Institution Case Series Alberto Morello, Marcello Scala, Irene Schiavetti, Maria Cristina Diana, and 4 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-3842470/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 06 Feb, 2024 Read the published version in Child's Nervous System → Version 1 posted 7 You are reading this latest preprint version Abstract Background The optimal timing and surgical approach for surgical revascularization in patients with Moyamoya syndrome (MMS) associated with Neurofibromatosis type I (NF1) remains so far elusive. We aimed to compare the long-term clinical, radiological, and cognitive effects of different revascularization procedures in a pediatric cohort of NF1-associated MMS. Methods We reviewed the clinical, radiological, and surgical data of 26 patients with NF1-associated MMS diagnosed at our Institution between 2012 and 2022, at the clinical onset and last follow-up. Results Indirect bypasses were performed in 12/26 patients (57.1%), while combined direct and indirect procedures in 9/26 subjects (42.9%); 5 patients did not undergo surgery. Through logistic regression analysis, pathological Wechsler Intelligence Scale for Children (WISC) at onset was found to be associated with symptom improvement at 1 year follow up (p =0.006). No significant differences were found in long-term neurocognitive outcome and stroke rate in patients receiving combined or indirect bypass (p>0.05). Conclusions Currently, whether combined or indirect bypass should be considered the treatment of choice in pediatric patients with NF1-associated MMS remains unclear, as well as the optimal time approach. In our series, no significant differences were found in long-term neurocognitive outcome and stroke rate between patients treated with either of these two approaches. Clinical evidence supports the crucial role of early diagnosis and surgical revascularization in subjects with MMS – associated NF1, even in case of mildly symptomatic vasculopathy. This allows to achieve a good long-term outcome with improved intellectual function, and prevention of stroke and seizure in these patients. Moyamoya disease NF1 cerebral stenosis revascularization bypass anastomosis Background The diagnosis of neurofibromatosis type 1 (NF1) is based on the clinical criteria established by the National Institutes of Health (NIH) Consensus Development Conference ( 1 ). In this condition, there is a large spectrum of central nervous system manifestations, including learning disability, mental retardation, seizures, attention-deficit with hyperkinesia disorder, optic nerve glioma, and extra-optic pathways tumors ( 2 ). Recent advances in the understanding of genotype-phenotype correlation are emerging concerning the association of cerebral vasculopathies in NF1. Vascular dysplasia is becoming increasingly emphasized as a feature of NF1 with an estimated frequency between 2 and 6% ( 3 ) ( 4 ). The exact pathogenesis of cerebral stenosis and Moyamoya syndrome (MMS) in patients with NF1 has not been elucidated yet ( 2 ). RNF213 gene mutations have been associated with MMD, but a recent analysis showed no direct involvement of NF213 variants in the pathogenesis of Moyamoya syndrome (MMS) in pediatric patients ( 5 ) ( 6 ). The main hypothesis is that the loss of neurofibromin, the protein encoded by the NF1 gene, in vascular endothelial cells may be responsible for the excessive proliferation of vascular smooth muscle cells causing stenosis of the carotid arteries ( 7 ) ( 5 ). Clinical manifestations of NF1 vasculopathy may stem from stenosis or occlusion of the vessels resulting in cerebral or visceral infarcts, aneurysms resulting in hemorrhage, or arteriovenous fistulae ( 8 ). In patients with NF1, the prevalence of MMS is estimated at around 0.6% ( 9 ). However, other authors reported a higher prevalence (3–6%), as most of the patients are often asymptomatic in the first stages of the disease ( 10 ), on the other hand, an increased mortality has been reported in patients with NF1 and vasculopathy ( 11 ). Patients with MMS, generally become symptomatic because of ischemic complications, leading to transient ischemic events, seizures, motor and sensory symptoms and neurocognitive deficits. The cognitive impairment is another important aspect to consider in patients with MMS. Indeed, on the basis of the natural history of NF1, approximately 80% of children develop deficits in one or more cognitive functions ( 12 ). Currently, there is no known medical treatment capable of reversing the progression of MMS. However, anticoagulants/antiplatelet agents and vasodilators are employed with the purpose of slowing the progression of the vasculopathy. Revascularization surgery has been shown to be a relatively safe and effective treatment for MMS. Revascularization prior to significant damage has been shown to improve cognition and quality of life, prevent neurocognitive decline if performed early, and to modulate the natural history of the disease ( 13 ) ( 14 ). The revascularization surgical approaches for MMS utilize branches of the preserved external carotid artery vasculature as donor vessels re-routed to augment blood flow to the ischemic territory of the affected internal carotid artery. This can be achieved either by direct or indirect revascularization methods. Direct revascularization involves direct vessel-to-vessel anastomosis of a branch of the external carotid artery, usually the superficial temporal artery to the internal carotid artery, or a more distal branch, usually the middle cerebral artery ( 15 ). The indirect method involves placing a vascularized pedicle graft from the external carotid artery over the surface of the brain to promote angiogenesis ( 16 ). Based on the tissue used, the main surgical techniques used are as follows: superficial temporal artery-middle cerebral artery (STA-MCA) bypass; encephalo-myo-synangiosis (EMS); encephalo-duro-synangiosis (EDAS) with dural graft; encephalo-duro-artero-myo-synangiosis (EDAMS); encephalo-duro-myo-arterio-pericranio-synangiosis (EDAMPS); encephalo-duro-arterio-pericranio-synangiosis (EDAPS) ( 17 ). Despite the evidence of a protective effect of surgical intervention in preventing poor cognitive outcome, especially if performed early in the disease course, there is no consensus about the ideal timing for revascularization surgery in NF1. Moreover, there are no randomized clinical trials in the literature comparing different revascularization techniques in children with NF1-associated MMS. Therefore, the surgical management of these cases is still performed on a case-based manner. The aim of our study is to compare the long-term clinical, radiological, and cognitive outcomes of children with NF1-associated MMS treated with different revascularization procedures, providing insights on technical features and timing of interventions. Methods This is a retrospective observational study conducted on patients with NF1-associated MMS diagnosed at the Gaslini Children’s Hospital between 2012 and 2022. Written informed consent was waived from the internal ethical committee due to the retrospective nature of the study. The study was conducted according to ethical standards laid down in the 1964 Declaration of Helsinki and its later amendments, following the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) guidelines. Basic demographics and clinical data were extracted from electronic medical records. Data about neurological signs and symptoms, cognitive status, and epilepsy were collected at presentation at 1/2/5-year follow-up. Information on other organ involvement and genetic data were reported when available. Neurosurgical data regarding the type and timing of surgical revascularization were reviewed by 2 pediatric neurosurgeons (A. M and M.P.). Cognitive impairment was studied by qualified neuropsychologists in each patient through the international scale: Wechsler Intelligence Scale for Children (WISC). Brain MRI studies were performed on 1.5T or 3T magnetic resonance scanners with different protocols, all including an axial diffusion weighted imaging (DWI), axial and coronal T2-weighted images, 2D or 3D T1-weighted images, 2D or 3D FLAIR images, intracranial arterial MR angiography (MRA), and brain MR perfusion studies with contrast (T2* DSC) and/or without contrast with arterial spin labeling (ASL) techniques. MR images were inspected in consensus by two expert and pediatric neuroradiologists (M.S. and D.T.) for the presence, type, and site of cerebral arteriopathies, cerebral tumors, neurofibromas, and focal areas of signal intensity (FASI). Statistic Statistical analysis was conducted using the Statistical Package for Social Sciences (SPSS) version 24.0. Continuous variables were presented as mean ± standard deviation (SD), while categorical variables were presented as counts with percentages. The effect of clinical data on the one-year outcomes (presence or absence of symptoms) was evaluated through logistic regression analysis. The findings are displayed as odds ratios (OR) alongside their respective 95% confidence intervals, and a p-value < 0.05 was considered statistically significant. Results Twenty-six ( 26 ) children with NF1-assicated MMS were enrolled in the study (15 females, 57.7%). The age at diagnosis ranged from 1 to 23 years (mean 8.0 ± 5.06 SD). Thirteen children were asymptomatic (12/26, 46.2%), while the most common symptoms were headache (5/26, 19.2%) and focal neurological deficits (5/26, 19.2%). 2 patients (7.7%) and 1 patient (3.8%) have manifested seizure and intellectual disability, respectively. 2 patients have experienced other symptoms (7.7%). Baseline characteristics are shown in Table 1. Imaging analysis At first MRI examination, the anterior circulation was involved in 25/26 (96.1%) cases with additional posterior cerebral artery stenosis in 7/26 subjects (26.9%). One subject had isolated posterior MMS (3.8%). Overall, the middle cerebral artery (MCA) was affected in 23 cases (88.5%), the internal carotid artery (ICA) in 13 (50%), the anterior cerebral artery (ACA) in 7 cases (26.9%), the posterior cerebral artery (PCA) in 8 patients (30.8%). Bilateral MMS was noted in 13/26 (50%) cases. Arterial ischemic infarcts were detected in 12 subjects (46.1%). The “ivy sign” on fluid-attenuated inversion recovery (FLAIR) or post-contrast T1-weighted images was found in 15 patients (15/26, 57.7%). Brain MR post-contrast perfusion studies were available in 23 cases and revealed delayed arterial transit time (ATT) in 21 cases (21/23, 91.3%), while reduced cerebral blood flow (CBF) was reduced in 4 subjects (4/23, 17,4%). Seven patients had an associated brain tumor (10/26, 38.4%). At last follow up, performed on average after 6 years (range 1–17 years), additional ischemic lesions were detected in 4 cases. At brain MR perfusion, the ATT delay improved in 18/23 (78.2%) cases, while one subject showed worsening of perfusion parameters (1/23, 4%). Treatment Immediately after the diagnosis of cerebral arteriopathy, 24 (92.3%) subjects were started with antiplatelet therapy. Twenty-one subjects underwent a surgical revascularization (21/26, 80.8%), including indirect bypasses in 12 cases (12/26, 57.1%) and combined direct and indirect procedures in 9 subjects (9/26, 42.9%). In particular, in the combined approaches STA-MCA + EMS + dural inversion was performed in 6 patients, STA -MCA + EMS was performed in 2 patients, STA-MCA e EMS left + EDAMPS right in 1 patient. On the other side, in the indirect approaches EDAS/EDAMPS was performed in 3 cases, EDAS in 3 patients, EDAMPS was performed in 3 patients, EDAPS in 1 patient, Burr Hole (other center) in 1 case, EDAS/EMS in 1 patient. Among the 5 subjects who did not undergo surgery (5/26, 19,2%), 3 patients refused surgery. The others were not operated because they had no symptoms and because there was no progression of stenosis/hypoperfusion at follow-up. The patients who underwent indirect bypass (n = 12) received acetylsalicylate therapy, (3–5 mg/kg/day, up to a maximum of 75–80 mg/day, according to Scott et al.), which was regularly stopped 5 days before surgery and replaced with low molecular weight heparin (LMWH) prophylaxis at 100 UI/kg ( 20 ). The acetylsalicylate therapy was restarted 48 h after surgery. The patients who underwent combined bypass (n = 9) received acetylsalicylate therapy, which was regularly stopped 24 hours before surgery and replaced 24/48 hours after surgery. Outcome At the time of diagnosis of arteriopathy, the cognitive deficit (pathologic Wechsler Intelligence Scale for Children -WISC) was present in 10 patients (10/26, 38.5%). The patients with pathologic WISC who refused the surgery (3/10), experienced disease progression (ischemic stroke ± seizure episodes) at 1/2 year follow-up. The remaining 7 patients with pathologic WISC, after by-pass surgery showed radiological and clinical evidence of stability (no stroke, hemorrhage, cognitive deterioration or progression stenosis) at 1/2 year of follow-up. The patients without cognitive deficit at the time of diagnosis (normal WISC) were 16 (61.5%). Cognitive deterioration at 1 year of follow-up was observed in 1 patient (1/16) who underwent previously EDAS/EDAMPS bilateral procedure. Progression stenosis at 1 year of follow-up occurred in 1 patient (1/16) who underwent previously STA-MCA + EMS + dural inversion unilateral procedure. The remaining 14 patients with normal WISC at the time of diagnosis, no stroke, hemorrhage, cognitive deterioration or progression stenosis occurred at 1 year of follow-up (4 of these remaining 14 patients didn’t undergo surgery). During the follow-up, 10 patients developed a brain tumor (7 optic pathway gliomas (OPG), 2 extra OPG, 1 OPG with extra-OPG). 5 patients received chemotherapy. 3 patients underwent radiotherapy and surgery tumor was performed in 4 cases. Through logistic regression analysis, pathological WISC at onset was identified as being associated with symptom improvement at 1 year follow up (p = 0.006) (Table 2 ). No significant differences were found in long-term neurocognitive outcome and stroke rate between combined and indirect bypass (p > 0.05) (Table 3 ). Discussion Children with NF1 manifest a wide spectrum of cerebrovascular abnormalities with an overall prevalence of approximately 2.5%, including narrowed or ectasic vessels, vascular stenoses, aneurysms, and Moyamoya framework ( 18 ) ( 2 ). On other hand, Moyamoya Disease (MMD) is characterized by bilateral steno-occlusive changes at the terminal portion of the ICA and an abnormal vascular network at the base of the brain. Patients with MMD present with the characteristic Moyamoya vasculopathy in the absence of associated risk factor. The etiology is unknown. MMD with unilateral involvement and no associated underlying disease has been defined probable MMD ( 19 ). If associated risk factors are present, the vasculopathy is defined MMS. This definition includes unilateral or bilateral cerebrovascular lesions in association with several underlying medical conditions, especially NF1, sickle cell disease, and Down syndrome ( 20 ). In such cases, MMS presents an extreme variability in terms of epidemiology, disease course, age of onset, progression, and complication rate. This picture is further complicated by the frequently unpredictable natural history of the underlying disorder and by the additional issues related to medical treatment. In the light of these considerations, a growing need for data about Moyamoya dysplasia-associated NF1 is emerging in order to delineate indications for revascularization surgery, especially in asymptomatic or mildly symptomatic cases. Epidemiology MMD has a higher incidence than MMS (0.35/100,000 versus 0.11/ 100,000, respectively) whereas the gender distribution (characterized by female predominance) is similar. Also similar to the non-NF1 population, there was a female preponderance in this series (15 females; 11 males). MMD is characterized by bilateral progressive stenosis or occlusion of the basal cerebral arteries, associated with abnormal net-like vessels at the base of the brain. On the other hand, a unilateral involvement may occur in MMS, in the literature in these patients, the vasculopathy is usually unilateral at the beginning and involves anterior vascular territories ( 21 ), ( 22 ). In our study, we noted that in 13 cases the vascular involvement was unilateral and we showed that the vascular unilateral involvement remained unilateral over time and there was no tendency to spread to the other side. According to literature review, based on 181 cases with NF1 and MMS between 1995 and 2015, the age at diagnosis of MMS in patients with NF1 varies dramatically among different series, with a median age ranging from 5.2 years ( 23 ) to 11.7 years ( 24 ). In our series of 26 patients, the mean age at diagnosis was 8.0 ± 5.06. Of interest also in the study by Rea et al was the presence of optic glioma in 13 of the 17 (76%) patients with arteriopathy, the majority having extensive tumors ( 23 ). In the present study, 7 patients had optic glioma, making the association of vasculopathy and optic glioma significant and rife for further study. Clinical manifestations Headache and focal neurological deficits were the most frequent presenting symptom in our series. All the patients experienced a gradual resolution of this symptom after the surgical treatment. In this regard, it has been hypothesized that headache could result from the stimulation of dural nociceptors by the compensatory dilatation of meningeal and leptomeningeal collateral vessels occurring in response to cerebral hypoperfusion ( 20 ). In contrast, occasional diagnoses without symptoms were 12 cases (46.2% of patients). This is probably due to the precise follow-up performed: every year children diagnosed with NF1 undergo a perfusion magnetic resonance imaging (p-MRI), and magnetic resonance angiography (MRA), in this way an acute event such as severe ischemia can be prevented (Supplementary Fig. 1). Radiology Radiographically, the MRI appearance of NF1-related and non-NF1 Moyamoya are indistinguishable, with both groups showing FLAIR hyperintensity (“ivy sign”) in underperfused cortex, a characteristic narrowing of the parent vessels in the anterior circulation of the brain, and in later stages, evidence of collateral formation and strokes in the same vascular distribution ( 25 ). At follow up, 18 cases were shown perfusion improved (18/24, 75.0%). Natural history of the underlying disease Children with NF1 who develop Moyamoya are 8 times more likely to be asymptomatic at the time of initial diagnosis than children with Moyamoya who do not have NF1—presumably secondary to the surveillance scanning performed in the NF1 population, thus increasing the probability of discovering Moyamoya as an incidental finding ( 26 ). In fact, a large proportion of our patients were also asymptomatic at the time of initial diagnosis. The development of MMS is a well-known complication of radiation therapy in patients with brain tumors ( 27 ). It has been shown that children with NF1 treated with radiation therapy are at increased risk for developing MMS and this risk is proportional to the radiation dose to the circle of Willis ( 26 ). Moreover, children with NF1 are potentially at increased risk for neurocognitive compromise after treatment with radiation ( 28 ). In addition, in the literature the perioperative stroke and complication rates were higher in patients who were treated with radiation despite similar rates of disease progression in patients with NF1 and Moyamoya who did not undergo radiation treatment, suggesting that other factors independent of Moyamoya may be contributing to the higher risk in this population. Of note, the administration of Selumetinib, a MAP kinase (MEK) 1/2 inhibitor which revealed helpful to treat NF1-associated tumors such as plexiform neurofibromas and optic way gliomas, has been recently associated with revascularization failure in NF1-related MMS ( 29 ). In contrast, in our study we demonstrated that complication rates in patients treated with cranial irradiation is low. For these reasons, it is necessary to valuate surgical revascularization in patients treated with cranial irradiation, even when the vascular disease is asymptomatic. In this way, we can achieve a good long-term outcome with improved intellectual function and prevention of stroke. Approximately 30% of patients with MMD have presented with involvement of the posterior circulation, mainly the posterior cerebral artery (PCA) ( 30 ). In MMS as NF1 the natural history is different because usually the worsening of posterior circle does not follow the anterior. The onset is dependent territory and the reason are unclear. Common is the symptomatology where headache is the most common symptom and ipsilateral to posterior cerebral artery stenosis or visual field oscillation hypoperfusion. After completion of the surgeries, patients in this study were followed up regularly in the outpatient clinic with the following imaging studies: p-MRI and MRA at 3–6 months after the last surgery; p-MRI and MRA every year thereafter. Cognitive impairment The cognitive impairment is another important aspect to consider in patients with MMS. Indeed, on the basis of the natural history of NF1, approximately 80% of children develop deficits in one or more cognitive functions ( 12 ). In addition, an increased frequency of attention deficit hyperactivity disorder (ADHD) and autistic spectrum disorders has also been observed in patients with NF1 and other RASopathies ( 31 ) ( 32 ). Studies on cognitive ability in these patients suggest that the prevalence of intellectual impairment (IQ < 70) is about 20% ( 33 ). The data on cognitive impairment in patients with MMS are still inconsistent and unsuitable to draw conclusions about the outcome after surgery or medical therapy alone. However, we can show that in post-operative of our series, 20 out 21 cases showed an intellectual stability quantifiable with the WISC scale at 1-2-5 year of follow-up. In this study, pathological WISC at onset was identified associated with symptom improvement at 1-year follow-up. This could play a role in the correct selection of patients for surgery. On the other hand, in order to have sufficient statistical power for other data, it is necessary to have a larger sample size to detect smaller effects. Timing of surgery The timing of diagnosis relative to the timing of surgery in the NF1- Moyamoya population is important. As noted above, many of the children in this series were diagnosed with Moyamoya while asymptomatic than comparable populations in non-NF1 Moyamoya, presumably related to the screening studies performed for other NF1-related pathology. There may be a lag of several months to years between the radiologic manifestations and the development of ischemic symptoms or signs secondary to NF1–associated cerebral vasculopathy ( 34 ). It has been established that clinical status at the time of Moyamoya diagnosis and surgery is the most important determinant of overall outcome ( 35 ). As such, there is a unique opportunity with these children to substantively reduce risk by treating them with early surgical intervention, prior to the onset of a debilitating stroke. This is also supported by the observations that many children developed clinical symptoms over time, and that radiographic progression occurred in 40% of patients; moreover, children who exhibited clinical symptoms preoperatively had the highest risks of perioperative complication ( 25 ). While clinicians need to exercise caution in confirming the diagnosis before committing a patient to surgery, and while the risks and benefits of each case must be determined individually, there is compelling evidence that reinforces the benefits of early diagnosis and justifies a proactive stance favoring early surgical revascularization. In our series we noted that there was only a clinical worsening case in cognitive outcome. We noted that in 20 cases there were not post-operative complications such as seizures, progression stenosis or ischemia at 1–2 follow-up. Revascularization prior to significant damage has been shown to improve cognition and quality of life, prevent neurocognitive decline if performed early, and to modulate the natural history of the disease ( 13 ). In fact, clinical evidence supports the crucial role of early diagnosis and surgical revascularization to achieve a good long-term outcome with improved intellectual function and stroke prevention in these patients ( 36 ) ( 37 ) ( 38 ). Some of these patients are affected by slow-growing tumors and need chemotherapy and/or RT, which both can worsen the vasculopathy. Considering the good prognosis of the associated tumors (e.g., OPGs) and that a delayed treatment usually does not affect the outcome, a prophylactic surgical revascularization should be considered in patients that must receive chemotherapy or RT and with initial cerebrovascular disease ( 27 ). Another aspect to be emphasized is that 3 cases of patients who refused surgery had a clinical worsening with episodes of ischemic stroke or convulsions in the follow-up. Surgical considerations Direct revascularization carries the risk of hyperperfusion syndrome, which results from a sudden increase in cerebral blood flow; the incidence is as high as 28% and is seen most often in patients with extensive preoperative ischemia ( 39 ) ( 40 ). Hyperperfusion syndrome can result in a temporary clinical picture that includes sensorimotor loss, aphasia, and dysarthria ( 41 ). Lastly, the procedure is challenging in the pediatric population because of the patients’ smaller, more delicate cerebral vasculature ( 21 ). Indirect techniques rely on tissue supplied by the external carotid artery, which is placed on the brain surface and promotes angiogenesis. This approach generally requires less operative time since it is both technically less challenging and less invasive ( 42 ). Importantly, the indirect approaches do not require temporary occlusion of MCA branches, which is required in the STA-MCA bypass ( 16 ). As such, indirect approaches have a better safety profile than direct procedures and are preferred in children and adults with other medical comorbidities ( 43 ). However, in stark contrast to children, collaterals only form in approximately half of the adult patients following the indirect procedures ( 44 ). Even then, collaterals take months to mature, while the direct procedures provide robust reperfusion immediately ( 45 ). Combined procedures have also been employed by some surgeons who have postulated that the technique reduces the incidence of repeat bleeding; however, there is little evidence to show if the outcomes are actually improved or potentially worsened ( 46 ). Thus, the literature does not present a clearly superior revascularization technique in the surgical management of MMD/MMS. Thus, our results currently offer the best comparison of the indirect and combined approaches. In our series, regarding the choice of the best surgical technique, no significant differences were found in long-term neurocognitive outcome and stroke rate between combined and indirect bypass. Additionally, reintervention was not necessary in any case. One of the distinct advantages of the indirect techniques is the ability to revascularize the anterior and posterior cerebral artery territories in addition to the middle cerebral artery territory, which is primarily targeted in the direct technique. This is especially important in the pediatric population who may have long-term neurologic dysfunction secondary to widespread hypoperfusion in the anterior, middle, and posterior cerebral artery territories. The process of revascularization and collateralization of the hypoperfused vascular bed is typically slow after the indirect techniques and may be associated with continued clinical symptoms for a period of usually a few months after the surgery. The reduced operative time and invasiveness, as well as the relative ease of the indirect procedures, may contribute to the well-documented decrease in adverse effects. Moreover, it is also possible that the risk of perioperative stroke from the delayed formation of collaterals following indirect procedures may be overstated. Our study noted that pediatric patients tolerated the combined procedure well and did not suffer from an in- creased rate of adverse events as compared with adult patients undergoing the direct procedure. Two procedures were determined to have equal efficacy, it stands to reason that the choice would be the less invasive approach. According to the good clinical and radiological results achieved by the surgical revascularization procedures performed under the Tokyo Daigaku (The University of Tokyo) protocol (TODAI protocol) in adult and pediatric patients with MMD (EDAS combined with EMS in patients 9 years old or younger; combined direct STA-MCA anastomosis and EMS in patients 10 years old or older) ( 47 ), we believe that EDAS combined with EMS should be considered an essential component of the surgical revascularization in children. Hemodynamic status Besides the importance of studying hemodynamic status, investigation of the collateral blood supply plays a pivotal role in evaluating a bypass indication since collateral blood flow influences perfusion and hemodynamics ( 48 ). The status of collateral circulation can be assessed with transcranial Doppler ultrasonography, CTA/MRA, and digital subtraction angiography. However, none of these modalities provide quantitative flow (ml/min) values. Therefore, quantitative 2D phase-contrast image analysis segments (NOVA software package) allows assessment of direction of blood flow and approximation of flow velocity ( 49 ). Another tool would be the Blood oxygen level-dependent (BOLD) MR imaging, a widely used technique for the noninvasive imaging of dynamic changes in CBF at the local and global levels ( 50 ). It can also be used to evaluate surgery in patients with an intermediate stage of disease (modified Suzuki stage II or III) and to follow patients after revascularization ( 51 ) ( 52 ). Comprehensively, BOLD MR provides a visual representation of ischemic risk and impending tissue demise. NOVA software and BOLD MR imaging are already used for example in the acute phase in the management of stroke due to Large Vessel Occlusion of the anterior circulation to better understand collateral circulation, as tool to decide if surgical revascularization would be an useful procedure ( 53 ). Perfusion in children with NF1 without MMS Since abnormal perfusion is expected in patients with MMS, we specifically targeted patients with NF-1 without this feature. Yeom et al demonstrated significantly lower CBF in patients with NF-1 compared with control subjects, occurring most prominently in the posterior circulation and the border zones of the middle and posterior cerebral arteries ( 54 ). To our knowledge, this is an important study to report perfusion abnormalities in children with NF-1 in the absence of prior strokes or underlying MMS. On the other hand cognitive complications are relatively common in NF-1, ranging from 30–65%, and include developmental delay, learning disabilities, attention deficit disorder, and headaches ( 12 ). If the relationship between NF-1 arteriopathy and cognitive involvement were clear, surgical revascularization could also play a role in NF-1 patients with abnormal perfusion, in the absence of a true Moyamoya diagnosis. Conclusion In this study, we reviewed our case series of patients with Moyamoya-associated NF1 and analyzed clinical, neuroimaging, and surgical data to investigate the role of surgical revascularization as a relevant procedure to prevent ischemic manifestations and neurocognitive decline in pediatric patients. Our study has some limitations. Indeed, it was not feasible to conduct a comprehensive follow-up for up to 5 years on all patients. Additionally, it’s important to note that this study might lack sufficient statistical power, suggesting the need for a larger sample size to detect statistically significant results when a real effect is present. A larger sample size would enhance the reliability and robustness of the study’s findings. Despite these limitations, our observations may have significant implications in the management of pediatric patients with Moyamoya-associated NF1. In patients diagnosed with NF1, we suggest yearly radiological follow-up through p-MRI e MRA, in order to prevent an acute event. In case of mild symptoms such as headache or hypoperfusion or stenosis progression, we recommend mono- or bilateral bypass surgery, depending on the vascular involvement and the clinic. We suggest considering prophylactic surgical revascularization in MMS patients with a good over- all prognosis and a cerebrovascular disease in early stages. In our opinion, this strategy could help prevent the deterioration of the cognitive function due to the progression of MMS. This protective surgery could offer the opportunity to preserve the quality of life of these patients, without any significant detrimental impact on the outcome. In addition, in our series, regarding the choice of the best surgical technique, no significant differences were found in long-term neurocognitive outcome and stroke rate between combined and indirect bypass. The decision to propose surgical cerebral revascularization may be difficult because many distinctive aspects have to be considered such as non-cerebral vasculopathy or in case of tumors in close proximity to the circle of Willis. Further multicentric studies are needed to shed some light on the treatment outcome in these complex patients due to the limited data available. Declarations Disclosures Conflict of Interest : The authors declare that the article and its content were composed in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. Grants and Support : This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. Conceptualization : Alberto Morello, Marco Pavanello; Methodology : Marco Pavanello; Formal analysis and investigation : Irene Schiavetti, Mariasavina Severino; Writing - original draft preparation : Alberto Morello; Writing - review and editing : Marcello Scala, Maria Cristina Diana, Domenico Tortora; Supervision : Marco Pavanello, Gianluca Piatelli. References Neurofibromatosis. Conference statement. National Institutes of Health Consensus Development Conference. Arch Neurol (1988) ;45(5):575–8 Scala M, Schiavetti I, Madia F, Chelleri C, Piccolo G, Accogli A et al (2021) Genotype-Phenotype Correlations in Neurofibromatosis Type 1: A Single-Center Cohort Study. Cancers (Basel). ;13(8) Cairns AG, North KN (2008) Cerebrovascular dysplasia in neurofibromatosis type 1. J Neurol Neurosurg Psychiatry 79(10):1165–1170 Friedman JM, Arbiser J, Epstein JA, Gutmann DH, Huot SJ, Lin AE et al (2002) Cardiovascular disease in neurofibromatosis 1: report of the NF1 Cardiovascular Task Force. 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Clin Genet 58(5):341–344 Katz DA, Marks MP, Napel SA, Bracci PM, Roberts SL (1995) Circle of Willis: evaluation with spiral CT angiography, MR angiography, and conventional angiography. Radiology 195(2):445–449 Lehrnbecher T, Gassel AM, Rauh V, Kirchner T, Huppertz HI (1994) Neurofibromatosis presenting as a severe systemic vasculopathy. Eur J Pediatr 153(2):107–109 Hyman SL, Shores A, North KN (2005) The nature and frequency of cognitive deficits in children with neurofibromatosis type 1. Neurology [Internet]. ;65(7):1037 LP – 1044. Available from: http://n.neurology.org/content/65/7/1037.abstract Guzman R, Lee M, Achrol A, Bell-Stephens T, Kelly M, Do HM et al (2009) Clinical outcome after 450 revascularization procedures for moyamoya disease. Clinical article. J Neurosurg 111(5):927–935 Lee JY, Phi JH, Wang K-C, Cho B-K, Shin M-S, Kim S-K (2011) Neurocognitive profiles of children with moyamoya disease before and after surgical intervention. 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N Engl J Med 360(12):1226–1237 Lin N, Baird L, Koss M, Kopecky KE, Gone E, Ullrich NJ et al (2011) Discovery of asymptomatic moyamoya arteriopathy in pediatric syndromic populations: radiographic and clinical progression. Neurosurg Focus 31(6):E6 Research Committee on the Pathology and Treatment of Spontaneous Occlusion of the Circle of Willis; Health Labour Sciences Research Grant for Research on Measures for Infractable Diseases (2012) Guidelines for diagnosis and treatment of moyamoya disease (spontaneous occlusion of the circle of Willis). Neurol Med Chir (Tokyo) 52(5):245–266 Rea D, Brandsema JF, Armstrong D, Parkin PC, deVeber G, MacGregor D et al (2009) Cerebral arteriopathy in children with neurofibromatosis type 1. Pediatrics 124(3):e476–e483 Crooks DR, Natarajan TG, Chen C, Huang H, Ghosh MC, Tong W-H et al (2012) Aberrant iron homeostasis, oxidative fiber enrichment, and activation of ketogenesis in muscle tissue of ISCU Myopathy patients. BMC Proc [Internet]. ;6. 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Dev Disabil Res Rev 14(3):229–237 Chelleri C, Scala M, De Marco P, Traverso M, Ognibene M, Bruno I et al (2023) Case report: Revascularization failure in NF1-related moyamoya syndrome after selumetinib: A possible pathophysiological correlation? Vol. 11, Frontiers in pediatrics. Switzerland; p. 1051026 Lee JY, Choi Y-H, Cheon J-E, Paeng JC, Ryu HW, Kim KJ et al (2014) Delayed posterior circulation insufficiency in pediatric moyamoya disease. J Neurol 261(12):2305–2313 Adviento B, Corbin IL, Widjaja F, Desachy G, Enrique N, Rosser T et al (2014) Autism traits in the RASopathies. J Med Genet 51(1):10–20 Miguel CS, Chaim-Avancini TM, Silva MA, Louzã MR (2015) Neurofibromatosis type 1 and attention deficit hyperactivity disorder: a case study and literature review. Neuropsychiatric disease and treatment, vol 11. New Zealand, pp 815–821 Allanson JE (2007) Noonan syndrome. 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Clin Neurol Neurosurg 99(Suppl 2):S11–S18 Fujimura M, Kaneta T, Mugikura S, Shimizu H, Tominaga T (2007) Temporary neurologic deterioration due to cerebral hyperperfusion after superficial temporal artery-middle cerebral artery anastomosis in patients with adult-onset moyamoya disease. Surg Neurol 67(3):273–282 Ishikawa T, Houkin K, Kamiyama H, Abe H (1997) Effects of surgical revascularization on outcome of patients with pediatric moyamoya disease. Stroke 28(6):1170–1173 Pandey P, Steinberg GK (2011) Neurosurgical advances in the treatment of moyamoya disease. Stroke 42(11):3304–3310 Zipfel GJ, Fox DJJ, Rivet DJ (2005) Moyamoya disease in adults: the role of cerebral revascularization. Skull Base 15(1):27–41 Chiu D, Shedden P, Bratina P, Grotta JC (1998) Clinical features of moyamoya disease in the United States. Stroke 29(7):1347–1351 Mizoi K, Kayama T, Yoshimoto T, Nagamine Y (1996) Indirect revascularization for moyamoya disease: is there a beneficial effect for adult patients? Surg Neurol 45(6):541–549 Macyszyn L, Attiah M, Ma TS, Ali Z, Faught R, Hossain A et al (2017) Direct versus indirect revascularization procedures for moyamoya disease: a comparative effectiveness study. J Neurosurg 126(5):1523–1529 Kuroda S, Houkin K, Ishikawa T, Nakayama N, Iwasaki Y (2010) Novel bypass surgery for moyamoya disease using pericranial flap: its impacts on cerebral hemodynamics and long-term outcome. Neurosurgery 66(6):1093–1101 discussion 1101 Imai H, Miyawaki S, Ono H, Nakatomi H, Yoshimoto Y, Saito N (2015) The importance of encephalo-myo-synangiosis in surgical revascularization strategies for moyamoya disease in children and adults. World Neurosurg 83(5):691–699 Bae YJ, Jung C, Kim JH, Choi BS, Kim E (2015) Quantitative Magnetic Resonance Angiography in Internal Carotid Artery Occlusion with Primary Collateral Pathway. J stroke 17(3):320–326 Lehman VT, Cogswell PM, Rinaldo L, Brinjikji W, Huston J, Klaas JP et al (2019) Contemporary and emerging magnetic resonance imaging methods for evaluation of moyamoya disease. Neurosurg Focus 47(6):E6 Dlamini N, Shah-Basak P, Leung J, Kirkham F, Shroff M, Kassner A et al (2018) Breath-Hold Blood Oxygen Level-Dependent MRI: A Tool for the Assessment of Cerebrovascular Reserve in Children with Moyamoya Disease. AJNR Am J Neuroradiol 39(9):1717–1723 Yun TJ, Cheon J-E, Na DG, Kim WS, Kim I-O, Chang K-H et al (2009) Childhood moyamoya disease: quantitative evaluation of perfusion MR imaging–correlation with clinical outcome after revascularization surgery. Radiology 251(1):216–223 Lee M, Zaharchuk G, Guzman R, Achrol A, Bell-Stephens T, Steinberg GK (2009) Quantitative hemodynamic studies in moyamoya disease: a review. Neurosurg Focus 26(4):E5 Sebök M, Esposito G, van Niftrik CHB, Fierstra J, Schubert T, Wegener S et al (2022) Flow augmentation STA-MCA bypass evaluation for patients with acute stroke and unilateral large vessel occlusion: a proposal for an urgent bypass flowchart. J Neurosurg. ;1–9 Yeom KW, Lober RM, Barnes PD, Campen CJ (2013) Reduced cerebral arterial spin-labeled perfusion in children with neurofibromatosis type 1. AJNR Am J Neuroradiol 34(9):1823–1828 Tables Tables 1 Baseline characteristics Descriptive N= 26 Sex, females 15 (57.7%) Age, years (DS) 8.0 ± 5.06 Ischemic infarct at onset (radiological) 12 (46.2%) Artery: MCA 23 (88.5%) Artery: ACA 7 (26.9%) Artery: ICA 13 (50.0%) Artery: PCA 8 (30.8%) Vascular involvement side Right 5 (19.2%) Left 8 (30.8%) Bilateral 13 (50.0%) Ivy signs 15 (57.7%) Delayed ATT (N = 23) 21 (91.3%) Reduced CBF (N = 23) 4 (17.4%) Side perfusion alteration (N = 21) Unilateral 10 (47.6%) Bilateral 11 (52.4%) Tumor 10 (38.5%) Tumor Type Optic Pathway Glioma 7 (70.0%) Extra-OPG 2 (20.0%) OPG & extra-OPG 1 (10.0%) Clinical score at onset Asymptomatic 12 (46.2%) At least one symptom 14 (53.8%) Clinical score at follow up Asymptomatic 12 (46.2%) One symptom 11 (42.3%) Two symptoms 2 (7.7%) Three symptoms 1 (3.8%) Initial symptom: Headache 5 (19.2%) Initial symptom: Focal neurological deficits 5 (19.2%) Initial symptom: Seizure 2 (7.7%) Initial symptom: Intellectual disability 1 (3.8%) Initial symptom: other 2 (7.7%) Cognitive onset (Pathologic WISC) Normal 16 (61.5%) Pathological 10 (38.5%) Radiological follow up duration, years 6.09 ± 4.32 MMD progression (N = 25) 16 (64.0%) Perfusion improved (N = 24) 18 (75.0%) Additional Ischemic infarcts (radiological, not clinical) at last follow up (N = 24) 4 (16.7%) CT 5 (19.2%) RT 3 (11.5%) Surgery Tumor 4 (15.4%) Medical Therapy 24 (92.3%) Surgery 21 (80.8%) Surgery Type (N = 21) Indirect 12 (57.1%) Combined 9 (42.9%) Technique (N = 21) STA-MCA+EMS+Dural inversion 6 (28.6%) STA-MCA + EMS 2 (9.5%) EDAS/EDAMPS 3 (14.3%) EDAS 3 (14.3%) EDAMPS 3 (14.3%) EDAPS 1 (4.8%) Burr Hole (other center) 1 (4.8%) EDAS + EMS 1 (4.8%) STA-MCA e EMS left + EDAMPS right 1 (4.8%) Associated vasculopathies 2 (7.7%) Type of vasculopathy PFO 1 RAS 1 Presence of symptoms at 1 year 4 (15.4%) DS= deviation standard; MCA= middle cerebral artery; ACA= anterior cerebral artery; ICA= internal carotid artery; PCA= posterior cerebral artery; ATT= arterial transit delay; CBF= cerebral blood flow; OPG= Optic Nerve Glioma; WISC= Wechsler Intelligence Scale for Children; MMD= Moyamoya disease; CT=chemotherapy; RT=radiotherapy; symptoms= headache, seizure, intellectual disability, focal neurological deficits; STA-MCA= superficial temporal artery-middle cerebral artery; EMS= encephalo-myo-synangiosis; EDAS= encephalo-duro-synangiosis; EDAMS= encephalo-duro-artero-myo-synangiosis; EDAMPS= encephalo-duro-myo-arterio-pericranio-synangiosis; PFO= patent foramen ovale; RAS= renal artery stenosis Table 2 Factors associated with improvement in symptoms at 1 Year No symptoms improvement Symptoms improvement OR (95%CI); p Sex Male 4 (36.4%) 7 (63.6%) M vs F: 2.63 (0.53 – 13.07); 0.24 Female 9 (60.0%) 6 (40.0%) Age (y) 9.6 ± 5.20 6.4 ± 4.56 0.86 (0.71 – 1.04); 0.13 Cognitive status at onset (Pathologic WISC) Normal 12 (75.0%) 4 (25.0%) 27.00 (2.56 – 284.70); 0.006 Pathologic 1 (10.0%) 9 (90.0%) By-pass No 3 (60.0%) 2 (40.0%) 1.65 (0.23 – 11.99); 0.62 Yes 10 (47.6%) 11 (52.4%) MCA No 1 (33.3%) 2 (66.7%) 0.46 (0.04 – 5.79); 0.55 Yes 12 (52.2%) 11 (47.8%) ACA No 11 (57.9%) 8 (42.1%) 3.44 (0.53 – 22.43); 0.20 Yes 2 (28.6%) 5 (71.4%) ICA No 7 (53.8%) 6 (46.2%) 1.36 (0.29 – 6.36); 0.70 Yes 6 (46.2%) 7 (53.8%) PCA No 11 (61.1%) 7 (38.9%) 4.71 (0.73 – 30.28); 0.10 Yes 2 (25.0%) 6 (75.0%) Tumor No 8 (50.0%) 8 (50.0%) 1.00 (0.21 – 4.86); 0.99 Yes 5 (50.0%) 5 (50.0%) Associated vasculopathies No 12 (50.0%) 12 (50.0%) 1.00 (0.06 – 17.90); 0.99 Yes 1 (50.0%) 1 (50.0%) Perfusion improved No 3 (50.0%) 3 (50.0%) 1.00 (0.16 – 6.35); 0.99 Yes 9 (50.0%) 9 (50.0%) MMD progression No 5 (55.6%) 4 (44.4%) 1.61 (0.31 – 8.32); 0.57 Yes 7 (43.8%) 9 (56.3%) WISC= Wechsler Intelligence Scale for Children; MCA= middle cerebral artery; ACA= anterior cerebral artery; ICA= internal carotid artery; PCA= posterior cerebral artery; Table 3 Outcome 1 year No symptoms Symptoms OR (95%CI); p Type of surgery Indirect 10 (55.6%) 2 (66.7%) 0.63 (0.05 - 8.20); 0.72 Combined 8 (44.4%) 1 (33.3%) Additional Declarations No competing interests reported. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-3842470","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":266073393,"identity":"6d067263-12ae-403d-8b6f-3ab027b9df71","order_by":0,"name":"Alberto Morello","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA80lEQVRIie3PsWrDMBCA4TOBZlGSVV6cJyicCagd9DAKBXkKdGyWIGNopuzJW/gVjKBe/ACGZHDpC7hbsuUKDoSA7LWD/kk3fJwOwOf7j43Z3dC8QwQQGHpyNxn9EdUNCmFBJCXD3eaRLM3Qmlk2KX7WZwnP2913o1Am+THbNi28blyE2+lbXCkNoioXqFCv8lORpvu+j1kmQqMsiFo/cYV2ldfLNGM9ZG7Zy6Uj4zORBIcI0pbgtoXOt2qQxHRLaLRmovoa0cd0fCBy2CMPjYNE5a74NVJGovwM2vZDzqd10tBjM3Oe38UeZhwCPp/P5+vrCk9CU3PGoRAHAAAAAElFTkSuQmCC","orcid":"","institution":"University of Turin","correspondingAuthor":true,"prefix":"","firstName":"Alberto","middleName":"","lastName":"Morello","suffix":""},{"id":266073394,"identity":"14c0c050-c7eb-4f1a-b493-3e02b5e02920","order_by":1,"name":"Marcello Scala","email":"","orcid":"","institution":"University of 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Gaslini","correspondingAuthor":false,"prefix":"","firstName":"Mariasavina","middleName":"","lastName":"Severino","suffix":""},{"id":266073398,"identity":"b3368684-cdb8-4b0a-8ef4-12f81c90b384","order_by":5,"name":"Domenico Tortora","email":"","orcid":"","institution":"IRCCS Istituto Giannina Gaslini","correspondingAuthor":false,"prefix":"","firstName":"Domenico","middleName":"","lastName":"Tortora","suffix":""},{"id":266073399,"identity":"55502688-d700-434e-b840-b087486bd972","order_by":6,"name":"Gianluca Piatelli","email":"","orcid":"","institution":"IRCCS Istituto Giannina Gaslini","correspondingAuthor":false,"prefix":"","firstName":"Gianluca","middleName":"","lastName":"Piatelli","suffix":""},{"id":266073400,"identity":"eced9310-817f-419c-8ccd-1a80c98f0d12","order_by":7,"name":"Marco Pavanello","email":"","orcid":"","institution":"IRCCS Istituto Giannina Gaslini","correspondingAuthor":false,"prefix":"","firstName":"Marco","middleName":"","lastName":"Pavanello","suffix":""}],"badges":[],"createdAt":"2024-01-07 12:29:14","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-3842470/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-3842470/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1007/s00381-024-06304-z","type":"published","date":"2024-02-06T15:01:02+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":51005800,"identity":"009090dc-d54b-4d98-a3e0-919ef39423f4","added_by":"auto","created_at":"2024-02-12 15:12:39","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":406617,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-3842470/v1/3e4a53dd-3b17-4841-99a2-de09c027572f.pdf"},{"id":49454278,"identity":"bc301374-e701-4dde-ad46-0bf654584e9c","added_by":"auto","created_at":"2024-01-11 06:03:54","extension":"docx","order_by":3,"title":"","display":"","copyAsset":false,"role":"supplement","size":24356,"visible":true,"origin":"","legend":"","description":"","filename":"SupplementaryContent1.docx","url":"https://assets-eu.researchsquare.com/files/rs-3842470/v1/2038a5df983516b6a1dee9c0.docx"}],"financialInterests":"No competing interests reported.","formattedTitle":"Surgical Revascularization as a Procedure to Prevent Neurological Complications in children with Moyamoya Syndrome Associated with Neurofibromatosis I: a Single Institution Case Series","fulltext":[{"header":"Background","content":"\u003cp\u003eThe diagnosis of neurofibromatosis type 1 (NF1) is based on the clinical criteria established by the National Institutes of Health (NIH) Consensus Development Conference (\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e). In this condition, there is a large spectrum of central nervous system manifestations, including learning disability, mental retardation, seizures, attention-deficit with hyperkinesia disorder, optic nerve glioma, and extra-optic pathways tumors (\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e). Recent advances in the understanding of genotype-phenotype correlation are emerging concerning the association of cerebral vasculopathies in NF1. Vascular dysplasia is becoming increasingly emphasized as a feature of NF1 with an estimated frequency between 2 and 6% (\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e) (\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e). The exact pathogenesis of cerebral stenosis and Moyamoya syndrome (MMS) in patients with NF1 has not been elucidated yet (\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e). RNF213 gene mutations have been associated with MMD, but a recent analysis showed no direct involvement of NF213 variants in the pathogenesis of Moyamoya syndrome (MMS) in pediatric patients (\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e) (\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e). The main hypothesis is that the loss of neurofibromin, the protein encoded by the NF1 gene, in vascular endothelial cells may be responsible for the excessive proliferation of vascular smooth muscle cells causing stenosis of the carotid arteries (\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e) (\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eClinical manifestations of NF1 vasculopathy may stem from stenosis or occlusion of the vessels resulting in cerebral or visceral infarcts, aneurysms resulting in hemorrhage, or arteriovenous fistulae (\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e). In patients with NF1, the prevalence of MMS is estimated at around 0.6% (\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e). However, other authors reported a higher prevalence (3\u0026ndash;6%), as most of the patients are often asymptomatic in the first stages of the disease (\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e), on the other hand, an increased mortality has been reported in patients with NF1 and vasculopathy (\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e). Patients with MMS, generally become symptomatic because of ischemic complications, leading to transient ischemic events, seizures, motor and sensory symptoms and neurocognitive deficits. The cognitive impairment is another important aspect to consider in patients with MMS. Indeed, on the basis of the natural history of NF1, approximately 80% of children develop deficits in one or more cognitive functions (\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e). Currently, there is no known medical treatment capable of reversing the progression of MMS. However, anticoagulants/antiplatelet agents and vasodilators are employed with the purpose of slowing the progression of the vasculopathy.\u003c/p\u003e \u003cp\u003eRevascularization surgery has been shown to be a relatively safe and effective treatment for MMS. Revascularization prior to significant damage has been shown to improve cognition and quality of life, prevent neurocognitive decline if performed early, and to modulate the natural history of the disease (\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e) (\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e). The revascularization surgical approaches for MMS utilize branches of the preserved external carotid artery vasculature as donor vessels re-routed to augment blood flow to the ischemic territory of the affected internal carotid artery. This can be achieved either by direct or indirect revascularization methods. Direct revascularization involves direct vessel-to-vessel anastomosis of a branch of the external carotid artery, usually the superficial temporal artery to the internal carotid artery, or a more distal branch, usually the middle cerebral artery (\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e). The indirect method involves placing a vascularized pedicle graft from the external carotid artery over the surface of the brain to promote angiogenesis (\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e). Based on the tissue used, the main surgical techniques used are as follows: superficial temporal artery-middle cerebral artery (STA-MCA) bypass; encephalo-myo-synangiosis (EMS); encephalo-duro-synangiosis (EDAS) with dural graft; encephalo-duro-artero-myo-synangiosis (EDAMS); encephalo-duro-myo-arterio-pericranio-synangiosis (EDAMPS); encephalo-duro-arterio-pericranio-synangiosis (EDAPS) (\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eDespite the evidence of a protective effect of surgical intervention in preventing poor cognitive outcome, especially if performed early in the disease course, there is no consensus about the ideal timing for revascularization surgery in NF1. Moreover, there are no randomized clinical trials in the literature comparing different revascularization techniques in children with NF1-associated MMS. Therefore, the surgical management of these cases is still performed on a case-based manner. The aim of our study is to compare the long-term clinical, radiological, and cognitive outcomes of children with NF1-associated MMS treated with different revascularization procedures, providing insights on technical features and timing of interventions.\u003c/p\u003e"},{"header":"Methods","content":"\u003cp\u003eThis is a retrospective observational study conducted on patients with NF1-associated MMS diagnosed at the Gaslini Children\u0026rsquo;s Hospital between 2012 and 2022. Written informed consent was waived from the internal ethical committee due to the retrospective nature of the study. The study was conducted according to ethical standards laid down in the 1964 Declaration of Helsinki and its later amendments, following the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) guidelines.\u003c/p\u003e \u003cp\u003eBasic demographics and clinical data were extracted from electronic medical records. Data about neurological signs and symptoms, cognitive status, and epilepsy were collected at presentation at 1/2/5-year follow-up. Information on other organ involvement and genetic data were reported when available. Neurosurgical data regarding the type and timing of surgical revascularization were reviewed by 2 pediatric neurosurgeons (A. M and M.P.). Cognitive impairment was studied by qualified neuropsychologists in each patient through the international scale: Wechsler Intelligence Scale for Children (WISC).\u003c/p\u003e \u003cp\u003eBrain MRI studies were performed on 1.5T or 3T magnetic resonance scanners with different protocols, all including an axial diffusion weighted imaging (DWI), axial and coronal T2-weighted images, 2D or 3D T1-weighted images, 2D or 3D FLAIR images, intracranial arterial MR angiography (MRA), and brain MR perfusion studies with contrast (T2* DSC) and/or without contrast with arterial spin labeling (ASL) techniques. MR images were inspected in consensus by two expert and pediatric neuroradiologists (M.S. and D.T.) for the presence, type, and site of cerebral arteriopathies, cerebral tumors, neurofibromas, and focal areas of signal intensity (FASI).\u003c/p\u003e\n\u003ch3\u003eStatistic\u003c/h3\u003e\n\u003cp\u003eStatistical analysis was conducted using the Statistical Package for Social Sciences (SPSS) version 24.0. Continuous variables were presented as mean\u0026thinsp;\u0026plusmn;\u0026thinsp;standard deviation (SD), while categorical variables were presented as counts with percentages. The effect of clinical data on the one-year outcomes (presence or absence of symptoms) was evaluated through logistic regression analysis. The findings are displayed as odds ratios (OR) alongside their respective 95% confidence intervals, and a p-value\u0026thinsp;\u0026lt;\u0026thinsp;0.05 was considered statistically significant.\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003eTwenty-six (\u003cspan class=\"CitationRef\"\u003e26\u003c/span\u003e) children with NF1-assicated MMS were enrolled in the study (15 females, 57.7%). The age at diagnosis ranged from 1 to 23 years (mean 8.0\u0026thinsp;\u0026plusmn;\u0026thinsp;5.06 SD). Thirteen children were asymptomatic (12/26, 46.2%), while the most common symptoms were headache (5/26, 19.2%) and focal neurological deficits (5/26, 19.2%). 2 patients (7.7%) and 1 patient (3.8%) have manifested seizure and intellectual disability, respectively. 2 patients have experienced other symptoms (7.7%). Baseline characteristics are shown in Table\u0026nbsp;1.\u003c/p\u003e\n\u003cdiv id=\"Sec5\" class=\"Section2\"\u003e\n\u003ch2\u003eImaging analysis\u003c/h2\u003e\n\u003cp\u003eAt first MRI examination, the anterior circulation was involved in 25/26 (96.1%) cases with additional posterior cerebral artery stenosis in 7/26 subjects (26.9%). One subject had isolated posterior MMS (3.8%). Overall, the middle cerebral artery (MCA) was affected in 23 cases (88.5%), the internal carotid artery (ICA) in 13 (50%), the anterior cerebral artery (ACA) in 7 cases (26.9%), the posterior cerebral artery (PCA) in 8 patients (30.8%). Bilateral MMS was noted in 13/26 (50%) cases. Arterial ischemic infarcts were detected in 12 subjects (46.1%). The \u0026ldquo;ivy sign\u0026rdquo; on fluid-attenuated inversion recovery (FLAIR) or post-contrast T1-weighted images was found in 15 patients (15/26, 57.7%). Brain MR post-contrast perfusion studies were available in 23 cases and revealed delayed arterial transit time (ATT) in 21 cases (21/23, 91.3%), while reduced cerebral blood flow (CBF) was reduced in 4 subjects (4/23, 17,4%). Seven patients had an associated brain tumor (10/26, 38.4%).\u003c/p\u003e\n\u003cp\u003eAt last follow up, performed on average after 6 years (range 1\u0026ndash;17 years), additional ischemic lesions were detected in 4 cases. At brain MR perfusion, the ATT delay improved in 18/23 (78.2%) cases, while one subject showed worsening of perfusion parameters (1/23, 4%).\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec6\" class=\"Section2\"\u003e\n\u003ch2\u003eTreatment\u003c/h2\u003e\n\u003cp\u003eImmediately after the diagnosis of cerebral arteriopathy, 24 (92.3%) subjects were started with antiplatelet therapy. Twenty-one subjects underwent a surgical revascularization (21/26, 80.8%), including indirect bypasses in 12 cases (12/26, 57.1%) and combined direct and indirect procedures in 9 subjects (9/26, 42.9%). In particular, in the combined approaches STA-MCA\u0026thinsp;+\u0026thinsp;EMS\u0026thinsp;+\u0026thinsp;dural inversion was performed in 6 patients, STA -MCA\u0026thinsp;+\u0026thinsp;EMS was performed in 2 patients, STA-MCA e EMS left\u0026thinsp;+\u0026thinsp;EDAMPS right in 1 patient. On the other side, in the indirect approaches EDAS/EDAMPS was performed in 3 cases, EDAS in 3 patients, EDAMPS was performed in 3 patients, EDAPS in 1 patient, Burr Hole (other center) in 1 case, EDAS/EMS in 1 patient. Among the 5 subjects who did not undergo surgery (5/26, 19,2%), 3 patients refused surgery. The others were not operated because they had no symptoms and because there was no progression of stenosis/hypoperfusion at follow-up.\u003c/p\u003e\n\u003cp\u003eThe patients who underwent indirect bypass (n\u0026thinsp;=\u0026thinsp;12) received acetylsalicylate therapy, (3\u0026ndash;5 mg/kg/day, up to a maximum of 75\u0026ndash;80 mg/day, according to Scott et al.), which was regularly stopped 5 days before surgery and replaced with low molecular weight heparin (LMWH) prophylaxis at 100 UI/kg (\u003cspan class=\"CitationRef\"\u003e20\u003c/span\u003e). The acetylsalicylate therapy was restarted 48 h after surgery. The patients who underwent combined bypass (n\u0026thinsp;=\u0026thinsp;9) received acetylsalicylate therapy, which was regularly stopped 24 hours before surgery and replaced 24/48 hours after surgery.\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv id=\"Sec7\" class=\"Section2\"\u003e\n\u003ch2\u003eOutcome\u003c/h2\u003e\n\u003cp\u003eAt the time of diagnosis of arteriopathy, the cognitive deficit (pathologic Wechsler Intelligence Scale for Children -WISC) was present in 10 patients (10/26, 38.5%). The patients with pathologic WISC who refused the surgery (3/10), experienced disease progression (ischemic stroke\u0026thinsp;\u0026plusmn;\u0026thinsp;seizure episodes) at 1/2 year follow-up. The remaining 7 patients with pathologic WISC, after by-pass surgery showed radiological and clinical evidence of stability (no stroke, hemorrhage, cognitive deterioration or progression stenosis) at 1/2 year of follow-up.\u003c/p\u003e\n\u003cp\u003eThe patients without cognitive deficit at the time of diagnosis (normal WISC) were 16 (61.5%). Cognitive deterioration at 1 year of follow-up was observed in 1 patient (1/16) who underwent previously EDAS/EDAMPS bilateral procedure. Progression stenosis at 1 year of follow-up occurred in 1 patient (1/16) who underwent previously STA-MCA\u0026thinsp;+\u0026thinsp;EMS\u0026thinsp;+\u0026thinsp;dural inversion unilateral procedure. The remaining 14 patients with normal WISC at the time of diagnosis, no stroke, hemorrhage, cognitive deterioration or progression stenosis occurred at 1 year of follow-up (4 of these remaining 14 patients didn\u0026rsquo;t undergo surgery).\u003c/p\u003e\n\u003cp\u003eDuring the follow-up, 10 patients developed a brain tumor (7 optic pathway gliomas (OPG), 2 extra OPG, 1 OPG with extra-OPG). 5 patients received chemotherapy. 3 patients underwent radiotherapy and surgery tumor was performed in 4 cases.\u003c/p\u003e\n\u003cp\u003eThrough logistic regression analysis, pathological WISC at onset was identified as being associated with symptom improvement at 1 year follow up (p\u0026thinsp;=\u0026thinsp;0.006) (Table\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003e).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eNo significant differences were found in long-term neurocognitive outcome and stroke rate between combined and indirect bypass (p\u0026thinsp;\u0026gt;\u0026thinsp;0.05) (Table\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e3\u003c/span\u003e).\u003c/p\u003e\n\u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003eChildren with NF1 manifest a wide spectrum of cerebrovascular abnormalities with an overall prevalence of approximately 2.5%, including narrowed or ectasic vessels, vascular stenoses, aneurysms, and Moyamoya framework (\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e) (\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e). On other hand, Moyamoya Disease (MMD) is characterized by bilateral steno-occlusive changes at the terminal portion of the ICA and an abnormal vascular network at the base of the brain. Patients with MMD present with the characteristic Moyamoya vasculopathy in the absence of associated risk factor. The etiology is unknown. MMD with unilateral involvement and no associated underlying disease has been defined probable MMD (\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e). If associated risk factors are present, the vasculopathy is defined MMS. This definition includes unilateral or bilateral cerebrovascular lesions in association with several underlying medical conditions, especially NF1, sickle cell disease, and Down syndrome (\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e). In such cases, MMS presents an extreme variability in terms of epidemiology, disease course, age of onset, progression, and complication rate. This picture is further complicated by the frequently unpredictable natural history of the underlying disorder and by the additional issues related to medical treatment. In the light of these considerations, a growing need for data about Moyamoya dysplasia-associated NF1 is emerging in order to delineate indications for revascularization surgery, especially in asymptomatic or mildly symptomatic cases.\u003c/p\u003e \u003cdiv id=\"Sec9\" class=\"Section2\"\u003e \u003ch2\u003eEpidemiology\u003c/h2\u003e \u003cp\u003eMMD has a higher incidence than MMS (0.35/100,000 versus 0.11/ 100,000, respectively) whereas the gender distribution (characterized by female predominance) is similar. Also similar to the non-NF1 population, there was a female preponderance in this series (15 females; 11 males). MMD is characterized by bilateral progressive stenosis or occlusion of the basal cerebral arteries, associated with abnormal net-like vessels at the base of the brain. On the other hand, a unilateral involvement may occur in MMS, in the literature in these patients, the vasculopathy is usually unilateral at the beginning and involves anterior vascular territories (\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e), (\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e). In our study, we noted that in 13 cases the vascular involvement was unilateral and we showed that the vascular unilateral involvement remained unilateral over time and there was no tendency to spread to the other side.\u003c/p\u003e \u003cp\u003eAccording to literature review, based on 181 cases with NF1 and MMS between 1995 and 2015, the age at diagnosis of MMS in patients with NF1 varies dramatically among different series, with a median age ranging from 5.2 years (\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e) to 11.7 years (\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e). In our series of 26 patients, the mean age at diagnosis was 8.0\u0026thinsp;\u0026plusmn;\u0026thinsp;5.06. Of interest also in the study by Rea et al was the presence of optic glioma in 13 of the 17 (76%) patients with arteriopathy, the majority having extensive tumors (\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e). In the present study, 7 patients had optic glioma, making the association of vasculopathy and optic glioma significant and rife for further study.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec10\" class=\"Section2\"\u003e \u003ch2\u003eClinical manifestations\u003c/h2\u003e \u003cp\u003eHeadache and focal neurological deficits were the most frequent presenting symptom in our series. All the patients experienced a gradual resolution of this symptom after the surgical treatment. In this regard, it has been hypothesized that headache could result from the stimulation of dural nociceptors by the compensatory dilatation of meningeal and leptomeningeal collateral vessels occurring in response to cerebral hypoperfusion (\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e). In contrast, occasional diagnoses without symptoms were 12 cases (46.2% of patients). This is probably due to the precise follow-up performed: every year children diagnosed with NF1 undergo a perfusion magnetic resonance imaging (p-MRI), and magnetic resonance angiography (MRA), in this way an acute event such as severe ischemia can be prevented (Supplementary Fig.\u0026nbsp;1).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec11\" class=\"Section2\"\u003e \u003ch2\u003eRadiology\u003c/h2\u003e \u003cp\u003eRadiographically, the MRI appearance of NF1-related and non-NF1 Moyamoya are indistinguishable, with both groups showing FLAIR hyperintensity (\u0026ldquo;ivy sign\u0026rdquo;) in underperfused cortex, a characteristic narrowing of the parent vessels in the anterior circulation of the brain, and in later stages, evidence of collateral formation and strokes in the same vascular distribution (\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e). At follow up, 18 cases were shown perfusion improved (18/24, 75.0%).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec12\" class=\"Section2\"\u003e \u003ch2\u003eNatural history of the underlying disease\u003c/h2\u003e \u003cp\u003eChildren with NF1 who develop Moyamoya are 8 times more likely to be asymptomatic at the time of initial diagnosis than children with Moyamoya who do not have NF1\u0026mdash;presumably secondary to the surveillance scanning performed in the NF1 population, thus increasing the probability of discovering Moyamoya as an incidental finding (\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e). In fact, a large proportion of our patients were also asymptomatic at the time of initial diagnosis.\u003c/p\u003e \u003cp\u003eThe development of MMS is a well-known complication of radiation therapy in patients with brain tumors (\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e). It has been shown that children with NF1 treated with radiation therapy are at increased risk for developing MMS and this risk is proportional to the radiation dose to the circle of Willis (\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e). Moreover, children with NF1 are potentially at increased risk for neurocognitive compromise after treatment with radiation (\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e). In addition, in the literature the perioperative stroke and complication rates were higher in patients who were treated with radiation despite similar rates of disease progression in patients with NF1 and Moyamoya who did not undergo radiation treatment, suggesting that other factors independent of Moyamoya may be contributing to the higher risk in this population. Of note, the administration of Selumetinib, a MAP kinase (MEK) 1/2 inhibitor which revealed helpful to treat NF1-associated tumors such as plexiform neurofibromas and optic way gliomas, has been recently associated with revascularization failure in NF1-related MMS (\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e). In contrast, in our study we demonstrated that complication rates in patients treated with cranial irradiation is low. For these reasons, it is necessary to valuate surgical revascularization in patients treated with cranial irradiation, even when the vascular disease is asymptomatic. In this way, we can achieve a good long-term outcome with improved intellectual function and prevention of stroke.\u003c/p\u003e \u003cp\u003eApproximately 30% of patients with MMD have presented with involvement of the posterior circulation, mainly the posterior cerebral artery (PCA) (\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e). In MMS as NF1 the natural history is different because usually the worsening of posterior circle does not follow the anterior. The onset is dependent territory and the reason are unclear. Common is the symptomatology where headache is the most common symptom and ipsilateral to posterior cerebral artery stenosis or visual field oscillation hypoperfusion.\u003c/p\u003e \u003cp\u003e After completion of the surgeries, patients in this study were followed up regularly in the outpatient clinic with the following imaging studies: p-MRI and MRA at 3\u0026ndash;6 months after the last surgery; p-MRI and MRA every year thereafter.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec13\" class=\"Section2\"\u003e \u003ch2\u003eCognitive impairment\u003c/h2\u003e \u003cp\u003eThe cognitive impairment is another important aspect to consider in patients with MMS. Indeed, on the basis of the natural history of NF1, approximately 80% of children develop deficits in one or more cognitive functions (\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e). In addition, an increased frequency of attention deficit hyperactivity disorder (ADHD) and autistic spectrum disorders has also been observed in patients with NF1 and other RASopathies (\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e) (\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e). Studies on cognitive ability in these patients suggest that the prevalence of intellectual impairment (IQ\u0026thinsp;\u0026lt;\u0026thinsp;70) is about 20% (\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e). The data on cognitive impairment in patients with MMS are still inconsistent and unsuitable to draw conclusions about the outcome after surgery or medical therapy alone. However, we can show that in post-operative of our series, 20 out 21 cases showed an intellectual stability quantifiable with the WISC scale at 1-2-5 year of follow-up. In this study, pathological WISC at onset was identified associated with symptom improvement at 1-year follow-up. This could play a role in the correct selection of patients for surgery. On the other hand, in order to have sufficient statistical power for other data, it is necessary to have a larger sample size to detect smaller effects.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec14\" class=\"Section2\"\u003e \u003ch2\u003eTiming of surgery\u003c/h2\u003e \u003cp\u003eThe timing of diagnosis relative to the timing of surgery in the NF1- Moyamoya population is important. As noted above, many of the children in this series were diagnosed with Moyamoya while asymptomatic than comparable populations in non-NF1 Moyamoya, presumably related to the screening studies performed for other NF1-related pathology. There may be a lag of several months to years between the radiologic manifestations and the development of ischemic symptoms or signs secondary to NF1\u0026ndash;associated cerebral vasculopathy (\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eIt has been established that clinical status at the time of Moyamoya diagnosis and surgery is the most important determinant of overall outcome (\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e). As such, there is a unique opportunity with these children to substantively reduce risk by treating them with early surgical intervention, prior to the onset of a debilitating stroke. This is also supported by the observations that many children developed clinical symptoms over time, and that radiographic progression occurred in 40% of patients; moreover, children who exhibited clinical symptoms preoperatively had the highest risks of perioperative complication (\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e). While clinicians need to exercise caution in confirming the diagnosis before committing a patient to surgery, and while the risks and benefits of each case must be determined individually, there is compelling evidence that reinforces the benefits of early diagnosis and justifies a proactive stance favoring early surgical revascularization. In our series we noted that there was only a clinical worsening case in cognitive outcome. We noted that in 20 cases there were not post-operative complications such as seizures, progression stenosis or ischemia at 1\u0026ndash;2 follow-up.\u003c/p\u003e \u003cp\u003eRevascularization prior to significant damage has been shown to improve cognition and quality of life, prevent neurocognitive decline if performed early, and to modulate the natural history of the disease (\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e). In fact, clinical evidence supports the crucial role of early diagnosis and surgical revascularization to achieve a good long-term outcome with improved intellectual function and stroke prevention in these patients (\u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e) (\u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e) (\u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eSome of these patients are affected by slow-growing tumors and need chemotherapy and/or RT, which both can worsen the vasculopathy. Considering the good prognosis of the associated tumors (e.g., OPGs) and that a delayed treatment usually does not affect the outcome, a prophylactic surgical revascularization should be considered in patients that must receive chemotherapy or RT and with initial cerebrovascular disease (\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e). Another aspect to be emphasized is that 3 cases of patients who refused surgery had a clinical worsening with episodes of ischemic stroke or convulsions in the follow-up.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec15\" class=\"Section2\"\u003e \u003ch2\u003eSurgical considerations\u003c/h2\u003e \u003cp\u003eDirect revascularization carries the risk of hyperperfusion syndrome, which results from a sudden increase in cerebral blood flow; the incidence is as high as 28% and is seen most often in patients with extensive preoperative ischemia (\u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e39\u003c/span\u003e) (\u003cspan citationid=\"CR40\" class=\"CitationRef\"\u003e40\u003c/span\u003e). Hyperperfusion syndrome can result in a temporary clinical picture that includes sensorimotor loss, aphasia, and dysarthria (\u003cspan citationid=\"CR41\" class=\"CitationRef\"\u003e41\u003c/span\u003e). Lastly, the procedure is challenging in the pediatric population because of the patients\u0026rsquo; smaller, more delicate cerebral vasculature (\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eIndirect techniques rely on tissue supplied by the external carotid artery, which is placed on the brain surface and promotes angiogenesis. This approach generally requires less operative time since it is both technically less challenging and less invasive (\u003cspan citationid=\"CR42\" class=\"CitationRef\"\u003e42\u003c/span\u003e). Importantly, the indirect approaches do not require temporary occlusion of MCA branches, which is required in the STA-MCA bypass (\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e). As such, indirect approaches have a better safety profile than direct procedures and are preferred in children and adults with other medical comorbidities (\u003cspan citationid=\"CR43\" class=\"CitationRef\"\u003e43\u003c/span\u003e). However, in stark contrast to children, collaterals only form in approximately half of the adult patients following the indirect procedures (\u003cspan citationid=\"CR44\" class=\"CitationRef\"\u003e44\u003c/span\u003e). Even then, collaterals take months to mature, while the direct procedures provide robust reperfusion immediately (\u003cspan citationid=\"CR45\" class=\"CitationRef\"\u003e45\u003c/span\u003e). Combined procedures have also been employed by some surgeons who have postulated that the technique reduces the incidence of repeat bleeding; however, there is little evidence to show if the outcomes are actually improved or potentially worsened (\u003cspan citationid=\"CR46\" class=\"CitationRef\"\u003e46\u003c/span\u003e). Thus, the literature does not present a clearly superior revascularization technique in the surgical management of MMD/MMS. Thus, our results currently offer the best comparison of the indirect and combined approaches. In our series, regarding the choice of the best surgical technique, no significant differences were found in long-term neurocognitive outcome and stroke rate between combined and indirect bypass. Additionally, reintervention was not necessary in any case.\u003c/p\u003e \u003cp\u003eOne of the distinct advantages of the indirect techniques is the ability to revascularize the anterior and posterior cerebral artery territories in addition to the middle cerebral artery territory, which is primarily targeted in the direct technique. This is especially important in the pediatric population who may have long-term neurologic dysfunction secondary to widespread hypoperfusion in the anterior, middle, and posterior cerebral artery territories. The process of revascularization and collateralization of the hypoperfused vascular bed is typically slow after the indirect techniques and may be associated with continued clinical symptoms for a period of usually a few months after the surgery. The reduced operative time and invasiveness, as well as the relative ease of the indirect procedures, may contribute to the well-documented decrease in adverse effects. Moreover, it is also possible that the risk of perioperative stroke from the delayed formation of collaterals following indirect procedures may be overstated. Our study noted that pediatric patients tolerated the combined procedure well and did not suffer from an in- creased rate of adverse events as compared with adult patients undergoing the direct procedure. Two procedures were determined to have equal efficacy, it stands to reason that the choice would be the less invasive approach.\u003c/p\u003e \u003cp\u003eAccording to the good clinical and radiological results achieved by the surgical revascularization procedures performed under the Tokyo Daigaku (The University of Tokyo) protocol (TODAI protocol) in adult and pediatric patients with MMD (EDAS combined with EMS in patients 9 years old or younger; combined direct STA-MCA anastomosis and EMS in patients 10 years old or older) (\u003cspan citationid=\"CR47\" class=\"CitationRef\"\u003e47\u003c/span\u003e), we believe that EDAS combined with EMS should be considered an essential component of the surgical revascularization in children.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec16\" class=\"Section2\"\u003e \u003ch2\u003eHemodynamic status\u003c/h2\u003e \u003cp\u003eBesides the importance of studying hemodynamic status, investigation of the collateral blood supply plays a pivotal role in evaluating a bypass indication since collateral blood flow influences perfusion and hemodynamics (\u003cspan citationid=\"CR48\" class=\"CitationRef\"\u003e48\u003c/span\u003e). The status of collateral circulation can be assessed with transcranial Doppler ultrasonography, CTA/MRA, and digital subtraction angiography. However, none of these modalities provide quantitative flow (ml/min) values. Therefore, quantitative 2D phase-contrast image analysis segments (NOVA software package) allows assessment of direction of blood flow and approximation of flow velocity (\u003cspan citationid=\"CR49\" class=\"CitationRef\"\u003e49\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eAnother tool would be the Blood oxygen level-dependent (BOLD) MR imaging, a widely used technique for the noninvasive imaging of dynamic changes in CBF at the local and global levels (\u003cspan citationid=\"CR50\" class=\"CitationRef\"\u003e50\u003c/span\u003e). It can also be used to evaluate surgery in patients with an intermediate stage of disease (modified Suzuki stage II or III) and to follow patients after revascularization (\u003cspan citationid=\"CR51\" class=\"CitationRef\"\u003e51\u003c/span\u003e) (\u003cspan citationid=\"CR52\" class=\"CitationRef\"\u003e52\u003c/span\u003e). Comprehensively, BOLD MR provides a visual representation of ischemic risk and impending tissue demise. NOVA software and BOLD MR imaging are already used for example in the acute phase in the management of stroke due to Large Vessel Occlusion of the anterior circulation to better understand collateral circulation, as tool to decide if surgical revascularization would be an useful procedure (\u003cspan citationid=\"CR53\" class=\"CitationRef\"\u003e53\u003c/span\u003e).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec17\" class=\"Section2\"\u003e \u003ch2\u003ePerfusion in children with NF1 without MMS\u003c/h2\u003e \u003cp\u003eSince abnormal perfusion is expected in patients with MMS, we specifically targeted patients with NF-1 without this feature. Yeom et al demonstrated significantly lower CBF in patients with NF-1 compared with control subjects, occurring most prominently in the posterior circulation and the border zones of the middle and posterior cerebral arteries (\u003cspan citationid=\"CR54\" class=\"CitationRef\"\u003e54\u003c/span\u003e). To our knowledge, this is an important study to report perfusion abnormalities in children with NF-1 in the absence of prior strokes or underlying MMS.\u003c/p\u003e \u003cp\u003eOn the other hand cognitive complications are relatively common in NF-1, ranging from 30\u0026ndash;65%, and include developmental delay, learning disabilities, attention deficit disorder, and headaches (\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e). If the relationship between NF-1 arteriopathy and cognitive involvement were clear, surgical revascularization could also play a role in NF-1 patients with abnormal perfusion, in the absence of a true Moyamoya diagnosis.\u003c/p\u003e \u003c/div\u003e"},{"header":"Conclusion","content":"\u003cp\u003eIn this study, we reviewed our case series of patients with Moyamoya-associated NF1 and analyzed clinical, neuroimaging, and surgical data to investigate the role of surgical revascularization as a relevant procedure to prevent ischemic manifestations and neurocognitive decline in pediatric patients. Our study has some limitations. Indeed, it was not feasible to conduct a comprehensive follow-up for up to 5 years on all patients. Additionally, it\u0026rsquo;s important to note that this study might lack sufficient statistical power, suggesting the need for a larger sample size to detect statistically significant results when a real effect is present. A larger sample size would enhance the reliability and robustness of the study\u0026rsquo;s findings.\u003c/p\u003e \u003cp\u003eDespite these limitations, our observations may have significant implications in the management of pediatric patients with Moyamoya-associated NF1. In patients diagnosed with NF1, we suggest yearly radiological follow-up through p-MRI e MRA, in order to prevent an acute event. In case of mild symptoms such as headache or hypoperfusion or stenosis progression, we recommend mono- or bilateral bypass surgery, depending on the vascular involvement and the clinic. We suggest considering prophylactic surgical revascularization in MMS patients with a good over- all prognosis and a cerebrovascular disease in early stages. In our opinion, this strategy could help prevent the deterioration of the cognitive function due to the progression of MMS. This protective surgery could offer the opportunity to preserve the quality of life of these patients, without any significant detrimental impact on the outcome. In addition, in our series, regarding the choice of the best surgical technique, no significant differences were found in long-term neurocognitive outcome and stroke rate between combined and indirect bypass.\u003c/p\u003e \u003cp\u003eThe decision to propose surgical cerebral revascularization may be difficult because many distinctive aspects have to be considered such as non-cerebral vasculopathy or in case of tumors in close proximity to the circle of Willis. Further multicentric studies are needed to shed some light on the treatment outcome in these complex patients due to the limited data available.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eDisclosures\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConflict of Interest\u003c/strong\u003e: The authors declare that the article and its content were composed in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eGrants and Support\u003c/strong\u003e: This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConceptualization\u003c/strong\u003e: Alberto Morello, Marco Pavanello;\u0026nbsp;\u003cstrong\u003eMethodology\u003c/strong\u003e: Marco Pavanello;\u0026nbsp;\u003cstrong\u003eFormal analysis and investigation\u003c/strong\u003e: Irene Schiavetti, Mariasavina Severino;\u0026nbsp;\u003cstrong\u003eWriting - original draft preparation\u003c/strong\u003e: Alberto Morello;\u0026nbsp;\u003cstrong\u003eWriting - review and editing\u003c/strong\u003e: Marcello Scala, Maria Cristina Diana, Domenico Tortora;\u0026nbsp;\u003cstrong\u003eSupervision\u003c/strong\u003e: Marco Pavanello, Gianluca Piatelli.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eNeurofibromatosis. 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Neurosurg Focus 26(4):E5\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSeb\u0026ouml;k M, Esposito G, van Niftrik CHB, Fierstra J, Schubert T, Wegener S et al (2022) Flow augmentation STA-MCA bypass evaluation for patients with acute stroke and unilateral large vessel occlusion: a proposal for an urgent bypass flowchart. J Neurosurg. ;1\u0026ndash;9\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eYeom KW, Lober RM, Barnes PD, Campen CJ (2013) Reduced cerebral arterial spin-labeled perfusion in children with neurofibromatosis type 1. AJNR Am J Neuroradiol 34(9):1823\u0026ndash;1828\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003e\u003cstrong\u003eTables 1 Baseline characteristics\u003c/strong\u003e\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"100%\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd width=\"100%\" colspan=\"3\" valign=\"bottom\"\u003e\n \u003cp\u003e\u003cstrong\u003eDescriptive N= 26\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"61.61616161616162%\" colspan=\"2\" valign=\"bottom\"\u003e\n \u003cp\u003eSex, females\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"38.38383838383838%\" valign=\"bottom\"\u003e\n \u003cp\u003e15 (57.7%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"61.61616161616162%\" colspan=\"2\" valign=\"bottom\"\u003e\n \u003cp\u003eAge, years (DS)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"38.38383838383838%\" valign=\"bottom\"\u003e\n \u003cp\u003e8.0 \u0026plusmn; 5.06\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"61.61616161616162%\" colspan=\"2\" valign=\"bottom\"\u003e\n \u003cp\u003eIschemic infarct at onset (radiological)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"38.38383838383838%\" valign=\"bottom\"\u003e\n \u003cp\u003e12 (46.2%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"61.61616161616162%\" colspan=\"2\" valign=\"bottom\"\u003e\n \u003cp\u003eArtery: MCA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"38.38383838383838%\" valign=\"bottom\"\u003e\n \u003cp\u003e23 (88.5%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"61.61616161616162%\" colspan=\"2\" valign=\"bottom\"\u003e\n \u003cp\u003eArtery: ACA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"38.38383838383838%\" valign=\"bottom\"\u003e\n \u003cp\u003e7 (26.9%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"61.61616161616162%\" colspan=\"2\" valign=\"bottom\"\u003e\n \u003cp\u003eArtery: ICA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"38.38383838383838%\" valign=\"bottom\"\u003e\n \u003cp\u003e13 (50.0%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"61.61616161616162%\" colspan=\"2\" valign=\"bottom\"\u003e\n \u003cp\u003eArtery: PCA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"38.38383838383838%\" valign=\"bottom\"\u003e\n \u003cp\u003e8 (30.8%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"36.734693877551024%\" rowspan=\"3\" valign=\"top\"\u003e\n \u003cp\u003eVascular involvement side\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"24.489795918367346%\" valign=\"top\"\u003e\n \u003cp\u003eRight\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"38.775510204081634%\" valign=\"top\"\u003e\n \u003cp\u003e5 (19.2%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"38.70967741935484%\" valign=\"top\"\u003e\n \u003cp\u003eLeft\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"61.29032258064516%\" valign=\"top\"\u003e\n \u003cp\u003e8 (30.8%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"38.70967741935484%\" valign=\"top\"\u003e\n \u003cp\u003eBilateral\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"61.29032258064516%\" valign=\"top\"\u003e\n \u003cp\u003e13 (50.0%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"61.61616161616162%\" colspan=\"2\" valign=\"top\"\u003e\n \u003cp\u003eIvy signs\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"38.38383838383838%\" valign=\"top\"\u003e\n \u003cp\u003e15 (57.7%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"61.61616161616162%\" colspan=\"2\" valign=\"top\"\u003e\n \u003cp\u003eDelayed ATT (N = 23)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"38.38383838383838%\" valign=\"top\"\u003e\n \u003cp\u003e21 (91.3%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"61.61616161616162%\" colspan=\"2\" valign=\"top\"\u003e\n \u003cp\u003eReduced CBF (N = 23)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"38.38383838383838%\" valign=\"top\"\u003e\n \u003cp\u003e4 (17.4%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"36.734693877551024%\" rowspan=\"2\" valign=\"top\"\u003e\n \u003cp\u003eSide perfusion alteration (N = 21)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"24.489795918367346%\" valign=\"top\"\u003e\n \u003cp\u003eUnilateral\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"38.775510204081634%\" valign=\"top\"\u003e\n \u003cp\u003e10 (47.6%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"38.70967741935484%\" valign=\"top\"\u003e\n \u003cp\u003eBilateral\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"61.29032258064516%\" valign=\"top\"\u003e\n \u003cp\u003e11 (52.4%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"36.734693877551024%\" valign=\"top\"\u003e\n \u003cp\u003eTumor\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"24.489795918367346%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"38.775510204081634%\" valign=\"top\"\u003e\n \u003cp\u003e10 (38.5%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"36.734693877551024%\" rowspan=\"3\" valign=\"top\"\u003e\n \u003cp\u003eTumor Type\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"24.489795918367346%\" valign=\"top\"\u003e\n \u003cp\u003eOptic Pathway Glioma\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"38.775510204081634%\" valign=\"top\"\u003e\n \u003cp\u003e7 (70.0%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"38.70967741935484%\" valign=\"top\"\u003e\n \u003cp\u003eExtra-OPG\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"61.29032258064516%\" valign=\"top\"\u003e\n \u003cp\u003e2 (20.0%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"38.70967741935484%\" valign=\"top\"\u003e\n \u003cp\u003eOPG \u0026amp; extra-OPG\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"61.29032258064516%\" valign=\"top\"\u003e\n \u003cp\u003e1 (10.0%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"36.734693877551024%\" rowspan=\"2\" valign=\"top\"\u003e\n \u003cp\u003eClinical score at onset\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"24.489795918367346%\" valign=\"top\"\u003e\n \u003cp\u003eAsymptomatic\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"38.775510204081634%\" valign=\"top\"\u003e\n \u003cp\u003e12 (46.2%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"38.70967741935484%\" valign=\"top\"\u003e\n \u003cp\u003eAt least one symptom\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"61.29032258064516%\" valign=\"top\"\u003e\n \u003cp\u003e14 (53.8%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"36.734693877551024%\" rowspan=\"4\" valign=\"top\"\u003e\n \u003cp\u003eClinical score at follow up\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"24.489795918367346%\" valign=\"top\"\u003e\n \u003cp\u003eAsymptomatic\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"38.775510204081634%\" valign=\"top\"\u003e\n \u003cp\u003e12 (46.2%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"38.70967741935484%\" valign=\"top\"\u003e\n \u003cp\u003eOne symptom\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"61.29032258064516%\" valign=\"top\"\u003e\n \u003cp\u003e11 (42.3%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"38.70967741935484%\" valign=\"top\"\u003e\n \u003cp\u003eTwo symptoms\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"61.29032258064516%\" valign=\"top\"\u003e\n \u003cp\u003e2 (7.7%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"38.70967741935484%\" valign=\"top\"\u003e\n \u003cp\u003eThree symptoms\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"61.29032258064516%\" valign=\"top\"\u003e\n \u003cp\u003e1 (3.8%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"36.734693877551024%\" valign=\"top\"\u003e\n \u003cp\u003eInitial symptom: Headache\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"24.489795918367346%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"38.775510204081634%\" valign=\"top\"\u003e\n \u003cp\u003e5 (19.2%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"36.734693877551024%\" valign=\"top\"\u003e\n \u003cp\u003eInitial symptom: Focal neurological deficits\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"24.489795918367346%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"38.775510204081634%\" valign=\"top\"\u003e\n \u003cp\u003e5 (19.2%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"36.734693877551024%\" valign=\"top\"\u003e\n \u003cp\u003eInitial symptom: Seizure\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"24.489795918367346%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"38.775510204081634%\" valign=\"top\"\u003e\n \u003cp\u003e2 (7.7%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"36.734693877551024%\" valign=\"top\"\u003e\n \u003cp\u003eInitial symptom: Intellectual disability\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"24.489795918367346%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"38.775510204081634%\" valign=\"top\"\u003e\n \u003cp\u003e1 (3.8%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"36.734693877551024%\" valign=\"top\"\u003e\n \u003cp\u003eInitial symptom: other\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"24.489795918367346%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"38.775510204081634%\" valign=\"top\"\u003e\n \u003cp\u003e2 (7.7%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"36.734693877551024%\" valign=\"top\"\u003e\n \u003cp\u003eCognitive onset (Pathologic WISC)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"24.489795918367346%\" valign=\"top\"\u003e\n \u003cp\u003eNormal\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"38.775510204081634%\" valign=\"top\"\u003e\n \u003cp\u003e16 (61.5%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"36.734693877551024%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"24.489795918367346%\" valign=\"top\"\u003e\n \u003cp\u003ePathological\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"38.775510204081634%\" valign=\"top\"\u003e\n \u003cp\u003e10 (38.5%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"36.734693877551024%\" valign=\"top\"\u003e\n \u003cp\u003eRadiological follow up duration, years\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"24.489795918367346%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"38.775510204081634%\" valign=\"top\"\u003e\n \u003cp\u003e6.09 \u0026plusmn; 4.32\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"36.734693877551024%\" valign=\"top\"\u003e\n \u003cp\u003eMMD progression\u0026nbsp;(N = 25)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"24.489795918367346%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"38.775510204081634%\" valign=\"top\"\u003e\n \u003cp\u003e16 (64.0%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"36.734693877551024%\" valign=\"top\"\u003e\n \u003cp\u003ePerfusion improved\u0026nbsp;(N = 24)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"24.489795918367346%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"38.775510204081634%\" valign=\"top\"\u003e\n \u003cp\u003e18 (75.0%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"36.734693877551024%\" valign=\"top\"\u003e\n \u003cp\u003eAdditional Ischemic infarcts (radiological, not clinical) at last follow up (N = 24)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"24.489795918367346%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"38.775510204081634%\" valign=\"top\"\u003e\n \u003cp\u003e4 (16.7%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"36.734693877551024%\" valign=\"top\"\u003e\n \u003cp\u003eCT\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"24.489795918367346%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"38.775510204081634%\" valign=\"top\"\u003e\n \u003cp\u003e5 (19.2%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"36.734693877551024%\" valign=\"top\"\u003e\n \u003cp\u003eRT\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"24.489795918367346%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"38.775510204081634%\" valign=\"top\"\u003e\n \u003cp\u003e3 (11.5%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"36.734693877551024%\" valign=\"top\"\u003e\n \u003cp\u003eSurgery Tumor\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"24.489795918367346%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"38.775510204081634%\" valign=\"top\"\u003e\n \u003cp\u003e4 (15.4%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"36.734693877551024%\" valign=\"top\"\u003e\n \u003cp\u003eMedical Therapy\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"24.489795918367346%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"38.775510204081634%\" valign=\"top\"\u003e\n \u003cp\u003e24 (92.3%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"36.734693877551024%\" valign=\"top\"\u003e\n \u003cp\u003eSurgery\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"24.489795918367346%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"38.775510204081634%\" valign=\"top\"\u003e\n \u003cp\u003e21 (80.8%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"36.734693877551024%\" rowspan=\"2\" valign=\"top\"\u003e\n \u003cp\u003eSurgery Type (N = 21)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"24.489795918367346%\" valign=\"top\"\u003e\n \u003cp\u003eIndirect\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"38.775510204081634%\" valign=\"top\"\u003e\n \u003cp\u003e12 (57.1%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"38.70967741935484%\" valign=\"top\"\u003e\n \u003cp\u003eCombined\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"61.29032258064516%\" valign=\"top\"\u003e\n \u003cp\u003e9 (42.9%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"36.734693877551024%\" rowspan=\"9\" valign=\"top\"\u003e\n \u003cp\u003eTechnique (N = 21)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"24.489795918367346%\" valign=\"top\"\u003e\n \u003cp\u003eSTA-MCA+EMS+Dural inversion\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"38.775510204081634%\" valign=\"top\"\u003e\n \u003cp\u003e6 (28.6%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"38.70967741935484%\" valign=\"top\"\u003e\n \u003cp\u003eSTA-MCA + EMS\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"61.29032258064516%\" valign=\"top\"\u003e\n \u003cp\u003e2 (9.5%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"38.70967741935484%\" valign=\"top\"\u003e\n \u003cp\u003eEDAS/EDAMPS\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"61.29032258064516%\" valign=\"top\"\u003e\n \u003cp\u003e3 (14.3%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"38.70967741935484%\" valign=\"top\"\u003e\n \u003cp\u003eEDAS\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"61.29032258064516%\" valign=\"top\"\u003e\n \u003cp\u003e3 (14.3%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"38.70967741935484%\" valign=\"top\"\u003e\n \u003cp\u003eEDAMPS\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"61.29032258064516%\" valign=\"top\"\u003e\n \u003cp\u003e3 (14.3%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"38.70967741935484%\" valign=\"top\"\u003e\n \u003cp\u003eEDAPS\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"61.29032258064516%\" valign=\"top\"\u003e\n \u003cp\u003e1 (4.8%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"38.70967741935484%\" valign=\"top\"\u003e\n \u003cp\u003eBurr Hole (other center)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"61.29032258064516%\" valign=\"top\"\u003e\n \u003cp\u003e1 (4.8%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"38.70967741935484%\" valign=\"top\"\u003e\n \u003cp\u003eEDAS + EMS\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"61.29032258064516%\" valign=\"top\"\u003e\n \u003cp\u003e1 (4.8%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"38.70967741935484%\" valign=\"top\"\u003e\n \u003cp\u003eSTA-MCA e EMS left + EDAMPS right\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"61.29032258064516%\" valign=\"top\"\u003e\n \u003cp\u003e1 (4.8%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"61.61616161616162%\" colspan=\"2\" valign=\"top\"\u003e\n \u003cp\u003eAssociated vasculopathies\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"38.38383838383838%\" valign=\"top\"\u003e\n \u003cp\u003e2 (7.7%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"36.734693877551024%\" rowspan=\"2\" valign=\"top\"\u003e\n \u003cp\u003eType of vasculopathy\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"24.489795918367346%\" valign=\"top\"\u003e\n \u003cp\u003ePFO\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"38.775510204081634%\" valign=\"top\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"38.70967741935484%\" valign=\"top\"\u003e\n \u003cp\u003eRAS\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"61.29032258064516%\" valign=\"top\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"36.734693877551024%\" valign=\"top\"\u003e\n \u003cp\u003ePresence of symptoms at 1 year\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"24.489795918367346%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"38.775510204081634%\" valign=\"top\"\u003e\n \u003cp\u003e4 (15.4%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eDS= deviation standard; MCA= middle cerebral artery; ACA= anterior cerebral artery; ICA= internal carotid artery; PCA= posterior cerebral artery; ATT= arterial transit delay; CBF= cerebral blood flow; OPG= Optic Nerve Glioma; WISC= Wechsler Intelligence Scale for Children; MMD= Moyamoya disease; CT=chemotherapy; RT=radiotherapy; symptoms= headache, seizure, intellectual disability, focal neurological deficits; STA-MCA= superficial temporal artery-middle cerebral artery; EMS= encephalo-myo-synangiosis; EDAS= encephalo-duro-synangiosis; EDAMS= encephalo-duro-artero-myo-synangiosis; EDAMPS= encephalo-duro-myo-arterio-pericranio-synangiosis; PFO= patent foramen ovale; \u0026nbsp;RAS= renal artery stenosis\u003c/p\u003e\n\u003cp\u003e\u003cbr\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 2 Factors associated with improvement in symptoms at 1 Year\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003ctable border=\"0\" cellspacing=\"0\" cellpadding=\"0\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\"\u003e\n \u003cp\u003eNo symptoms improvement\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\"\u003e\n \u003cp\u003eSymptoms improvement\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eOR (95%CI); p\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"2\" valign=\"top\"\u003e\n \u003cp\u003eSex\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eMale\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\"\u003e\n \u003cp\u003e4 (36.4%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\"\u003e\n \u003cp\u003e7 (63.6%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\"\u003e\n \u003cp\u003eM vs F: 2.63 (0.53 \u0026ndash; 13.07); 0.24\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eFemale\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\"\u003e\n \u003cp\u003e9 (60.0%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\"\u003e\n \u003cp\u003e6 (40.0%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eAge (y)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\"\u003e\n \u003cp\u003e9.6 \u0026plusmn; 5.20\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\"\u003e\n \u003cp\u003e6.4 \u0026plusmn; 4.56\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.86 (0.71 \u0026ndash; 1.04); 0.13\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"2\" valign=\"top\"\u003e\n \u003cp\u003eCognitive status at onset (Pathologic WISC)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eNormal\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\"\u003e\n \u003cp\u003e12 (75.0%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\"\u003e\n \u003cp\u003e4 (25.0%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\"\u003e\n \u003cp\u003e27.00 (2.56 \u0026ndash; 284.70); 0.006\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003ePathologic\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\"\u003e\n \u003cp\u003e1 (10.0%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"bottom\"\u003e\n \u003cp\u003e9 (90.0%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"2\" valign=\"top\"\u003e\n \u003cp\u003eBy-pass\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e3 (60.0%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e2 (40.0%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\"\u003e\n \u003cp\u003e1.65 (0.23 \u0026ndash; 11.99); 0.62\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e10 (47.6%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e11 (52.4%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"2\" valign=\"top\"\u003e\n \u003cp\u003eMCA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e1 (33.3%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e2 (66.7%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\"\u003e\n \u003cp\u003e0.46 (0.04 \u0026ndash; 5.79); 0.55\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e12 (52.2%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e11 (47.8%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"2\" valign=\"top\"\u003e\n \u003cp\u003eACA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e11 (57.9%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e8 (42.1%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\"\u003e\n \u003cp\u003e3.44 (0.53 \u0026ndash; 22.43); 0.20\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e2 (28.6%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e5 (71.4%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"2\" valign=\"top\"\u003e\n \u003cp\u003eICA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e7 (53.8%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e6 (46.2%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\"\u003e\n \u003cp\u003e1.36 (0.29 \u0026ndash; 6.36); 0.70\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e6 (46.2%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e7 (53.8%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"2\" valign=\"top\"\u003e\n \u003cp\u003ePCA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e11 (61.1%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e7 (38.9%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\"\u003e\n \u003cp\u003e4.71 (0.73 \u0026ndash; 30.28); 0.10\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e2 (25.0%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e6 (75.0%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"2\" valign=\"top\"\u003e\n \u003cp\u003eTumor\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e8 (50.0%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e8 (50.0%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\"\u003e\n \u003cp\u003e1.00 (0.21 \u0026ndash; 4.86); 0.99\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e5 (50.0%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e5 (50.0%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"2\" valign=\"top\"\u003e\n \u003cp\u003eAssociated vasculopathies\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e12 (50.0%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e12 (50.0%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\"\u003e\n \u003cp\u003e1.00 (0.06 \u0026ndash; 17.90); 0.99\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e1 (50.0%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e1 (50.0%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"2\" valign=\"top\"\u003e\n \u003cp\u003ePerfusion improved\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e3 (50.0%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e3 (50.0%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\"\u003e\n \u003cp\u003e1.00 (0.16 \u0026ndash; 6.35); 0.99\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e9 (50.0%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e9 (50.0%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"2\" valign=\"top\"\u003e\n \u003cp\u003eMMD progression\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eNo\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e5 (55.6%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e4 (44.4%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\"\u003e\n \u003cp\u003e1.61 (0.31 \u0026ndash; 8.32); 0.57\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eYes\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e7 (43.8%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e9 (56.3%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eWISC= Wechsler Intelligence Scale for Children; MCA= middle cerebral artery; ACA= anterior cerebral artery; ICA= internal carotid artery; PCA= posterior cerebral artery;\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 3\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003eOutcome 1 year\u003c/strong\u003e\u003c/p\u003e\n\u003ctable border=\"0\" cellspacing=\"0\" cellpadding=\"0\" align=\"left\" width=\"100%\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd width=\"21.649484536082475%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.43298969072165%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.556701030927837%\" valign=\"bottom\"\u003e\n \u003cp\u003eNo symptoms\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.463917525773196%\" valign=\"bottom\"\u003e\n \u003cp\u003eSymptoms\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"29.896907216494846%\" valign=\"top\"\u003e\n \u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp;OR (95%CI); p\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"21.649484536082475%\" rowspan=\"2\" valign=\"top\"\u003e\n \u003cp\u003eType of surgery\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"14.43298969072165%\" valign=\"top\"\u003e\n \u003cp\u003eIndirect\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"18.556701030927837%\" valign=\"top\"\u003e\n \u003cp\u003e10 (55.6%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.463917525773196%\" valign=\"top\"\u003e\n \u003cp\u003e2 (66.7%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"29.896907216494846%\" rowspan=\"2\" valign=\"top\"\u003e\n \u003cp\u003e0.63 (0.05 - 8.20); 0.72\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"29.78723404255319%\" valign=\"top\"\u003e\n \u003cp\u003eCombined\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"38.297872340425535%\" valign=\"top\"\u003e\n \u003cp\u003e8 (44.4%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"31.914893617021278%\" valign=\"top\"\u003e\n \u003cp\u003e1 (33.3%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"childs-nervous-system","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"cnsy","sideBox":"Learn more about [Child's Nervous System](http://link.springer.com/journal/381)","snPcode":"381","submissionUrl":"https://submission.nature.com/new-submission/381/3","title":"Child's Nervous System","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"Moyamoya disease, NF1, cerebral stenosis, revascularization, bypass, anastomosis","lastPublishedDoi":"10.21203/rs.3.rs-3842470/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-3842470/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground \u003c/strong\u003eThe optimal timing and surgical approach for surgical revascularization in patients with Moyamoya syndrome (MMS) associated with Neurofibromatosis type I (NF1) remains so far elusive. We aimed to compare the long-term clinical, radiological, and cognitive effects of different revascularization procedures in a pediatric cohort of NF1-associated MMS.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods \u003c/strong\u003eWe reviewed the clinical, radiological, and surgical data of 26 patients with NF1-associated MMS diagnosed at our Institution between 2012 and 2022, at the clinical onset and last follow-up.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults \u003c/strong\u003eIndirect bypasses were performed in 12/26 patients (57.1%), while combined direct and indirect procedures in 9/26 subjects (42.9%); 5 patients did not undergo surgery. Through logistic regression analysis, pathological Wechsler Intelligence Scale for Children (WISC) at onset was found to be associated with symptom improvement at 1 year follow up (p =0.006). No significant differences were found in long-term neurocognitive outcome and stroke rate in patients receiving combined or indirect bypass (p\u0026gt;0.05).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusions \u003c/strong\u003eCurrently, whether combined or indirect bypass should be considered the treatment of choice in pediatric patients with NF1-associated MMS remains unclear, as well as the optimal time approach. In our series, no significant differences were found in long-term neurocognitive outcome and stroke rate between patients treated with either of these two approaches. Clinical evidence supports the crucial role of early diagnosis and surgical revascularization in subjects with MMS – associated NF1, even in case of mildly symptomatic vasculopathy. This allows to achieve a good long-term outcome with improved intellectual function, and prevention of stroke and seizure in these patients.\u003c/p\u003e","manuscriptTitle":"Surgical Revascularization as a Procedure to Prevent Neurological Complications in children with Moyamoya Syndrome Associated with Neurofibromatosis I: a Single Institution Case Series","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-01-11 06:03:49","doi":"10.21203/rs.3.rs-3842470/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Accepted","date":"2024-01-24T15:48:37+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2024-01-24T10:05:23+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"f48935a0-1f60-479b-9556-f686e87f5040","date":"2024-01-17T08:27:14+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2024-01-15T19:35:09+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2024-01-09T09:56:39+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2024-01-09T09:56:39+00:00","index":"","fulltext":""},{"type":"submitted","content":"Child's Nervous System","date":"2024-01-07T12:27:49+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"childs-nervous-system","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"cnsy","sideBox":"Learn more about [Child's Nervous System](http://link.springer.com/journal/381)","snPcode":"381","submissionUrl":"https://submission.nature.com/new-submission/381/3","title":"Child's Nervous System","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"a5b89480-d60a-432f-a405-33b7b732498a","owner":[],"postedDate":"January 11th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2024-02-12T15:07:59+00:00","versionOfRecord":{"articleIdentity":"rs-3842470","link":"https://doi.org/10.1007/s00381-024-06304-z","journal":{"identity":"childs-nervous-system","isVorOnly":false,"title":"Child's Nervous System"},"publishedOn":"2024-02-06 15:01:02","publishedOnDateReadable":"February 6th, 2024"},"versionCreatedAt":"2024-01-11 06:03:49","video":"","vorDoi":"10.1007/s00381-024-06304-z","vorDoiUrl":"https://doi.org/10.1007/s00381-024-06304-z","workflowStages":[]},"version":"v1","identity":"rs-3842470","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-3842470","identity":"rs-3842470","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}