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OBJECTIVE The purpose of this study was to evaluate the safety of oligodendrocyte progenitor cells (LCTOPC1) derived from human pluripotent stem cells administered between 7 and 14 days postinjury to patients with T3 to T11 neurologically complete spinal cord injury (SCI). The rationale for this first-in-human trial was based on evidence that administration of LCTOPC1 supports survival and potential repair of key cellular components and architecture at the SCI site. METHODS This study was a multisite, open-label, single-arm interventional clinical trial. Participants (n = 5) received a single intraparenchymal injection of 2 × 106 LCTOPC1 caudal to the epicenter of injury using a syringe positioning device. Immunosuppression with tacrolimus was administered for a total of 60 days. Participants were followed with annual in-person examinations and MRI for 5 years at the time of this report and will be followed with annual telephone questionnaires for 6 to 15 years postinjection. The primary endpoint was safety, as measured by the frequency and severity of adverse events related to the LCTOPC1 injection, the injection procedure, and/or the concomitant immunosuppression administered. The secondary endpoint was neurological function as measured by sensory scores and lower-extremity motor scores as measured by the International Standards for Neurological Classification of Spinal Cord Injury examinations. RESULTS No unanticipated serious adverse events related to LCTOPC1 have been reported with 98% follow-up of participants (49 of 50 annual visits) through the first 10 years of the clinical trial. There was no evidence of neurological decline, enlarging masses, further spinal cord damage, or syrinx formation. MRI results during the long-term follow-up period in patients administered LCTOPC1 cells showed that 80% of patients demonstrated T2 signal changes consistent with the formation of a tissue matrix at the injury site. CONCLUSIONS This study provides crucial first-in-human safety data supporting the pursuit of future human embryonic stem cell–derived therapies. While we cannot exclude the possibility of future adverse events, the experience in this trial provides evidence that this cell type can be well tolerated by patients, with an event-free period of up to 10 years. Based on the safety profile of LCTOPC1 obtained in this study, a cervical dose escalation trial was initiated (NCT02302157).

Moya Moya disease (MMD) and Moya Moya syndrome (MMS) are cerebrovascular disorders, which affect the internal carotid arteries (ICAs). Diagnosis and surveillance of MMD/MMS in children mostly rely on qualitative evaluation of vascular imaging, especially MR angiography (MRA).To quantitatively characterize arterial differences in pediatric patients with MMD/MMS compared with normal controls.MRA data sets from 17 presurgery MMD/MMS (10M/7F, mean age = 10.0 years) patients were retrospectively collected and compared with MRA data sets of 98 children with normal vessel morphology (49 male patients; mean age = 10.6 years). Using a level set segmentation method with anisotropic energy weights, the cerebral arteries were automatically extracted and used to compute the radius of the ICA, middle cerebral artery (MCA), anterior cerebral artery (ACA), posterior cerebral artery (PCA), and basilar artery (BA). Moreover, the density and the average radius of all arteries in the MCA, ACA, and PCA flow territories were quantified.Statistical analysis revealed significant differences comparing children with MMD/MMS and those with normal vasculature ( P.001), whereas post hoc analyses identified significantly smaller radii of the ICA, MCA-M1, MCA-M2, and ACA ( P.001) in the MMD/MMS group. No significant differences were found for the radii of the PCA and BA or any artery density and average artery radius measurement in the flow territories ( P.05).His study describes the results of an automatic approach for quantitative characterization of the cerebrovascular system in patients with MMD/MMS with promising preliminary results for quantitative surveillance in pediatric MMD/MMS management.

Moyamoya disease is a rare cause of stroke, radiologically characterised by progressive stenosis of the terminal portion of the internal carotid arteries and compensatory capillary collaterals. The discovery that RNF213, which encodes an unconventional E3 ubiquitin ligase, is the major susceptibility gene for moyamoya disease in people from east Asia has opened new avenues for investigation into the mechanisms of disease and potential treatment targets. The Arg4810Lys variant of the gene is most strongly associated with moyamoya disease, but the penetrance is lower than 1%, suggesting a synergistic relationship with additional environmental and genetic risk factors. White people carry less common non-Arg4810Lys variants of RNF213, which partly explains the lower prevalence of moyamoya disease in European countries and in the USA than in east Asian countries. Several monogenic moyamoya syndromes possess the radiological characteristics of moyamoya disease and have been associated with multiple genes and pathways involved in moyamoya angiopathy pathogenesis. Further clarification of the genetic and environmental factors that contribute to the emergence of moyamoya angiopathy could enable development of new treatment strategies for moyamoya disease.

BACKGROUND Schizencephaly is an uncommon central nervous system malformation. Intracranial lipomas are also rare, accounting for approximately 0.1% of brain “tumors.” They are believed to be derived from a persistent meninx primitiva, a neural crest–derived mesenchyme that develops into the dura and leptomeninges. OBSERVATIONS The authors present a case of heterotopic adipose tissue and a nonshunting arterial vascular malformation arising within a schizencephalic cleft in a 22-year-old male. Imaging showed right frontal gray matter abnormality and an associated suspected arteriovenous malformation with evidence of hemorrhage. Brain magnetic resonance imaging revealed right frontal polymicrogyria lining an open-lip schizencephaly, periventricular heterotopic gray matter, fat within the schizencephalic cleft, and gradient echo hypointensity concerning for prior hemorrhage. Histological assessment demonstrated mature adipose tissue with large-bore, thick-walled, irregular arteries. Mural calcifications and subendothelial cushions suggesting nonlaminar blood flow were observed. There were no arterialized veins or direct transitions from the arteries to veins. Hemosiderin deposition was scant, and hemorrhage was not present. The final diagnosis was consistent with ectopic mature adipose tissue and arteries with meningocerebral cicatrix. LESSONS This example of a complex maldevelopment of derivatives of the meninx primitiva in association with cortical maldevelopment highlights the unique challenges from both a radiological and histological perspective during diagnostic workup.

Background: Cerebrovascular reserve (CVR) inversely correlates with stroke risk in children with Moyamoya disease and may be improved by revascularization surgery. We hypothesized that acetazolamide-challenged arterial spin labeling MR perfusion quantifies augmentation of CVR achieved by revascularization and correlates with currently accepted angiographic scoring criteria. Methods: We retrospectively identified pediatric patients with Moyamoya disease or syndrome who received cerebral revascularization at ≤18 years of age between 2012 and 2019 at our institution. Using acetazolamide-challenged arterial spin labeling, we compared postoperative CVR to corresponding preoperative values and to postoperative perfusion outcomes classified by Matsushima grading. Results: In this cohort, 32 patients (17 males) with Moyamoya underwent 29 direct and 16 indirect extracranial-intracranial bypasses at a median 9.7 years of age (interquartile range, 7.6–15.7). Following revascularization, median CVR increased within the ipsilateral middle cerebral artery territory (6.9 mL/100 g per minute preoperatively versus 16.5 mL/100 g per minute postoperatively, P P =0.13) and posterior cerebral artery ( P =0.48) territories. Postoperative CVR was higher in the ipsilateral middle cerebral artery territories of patients who achieved Matsushima grade A perfusion, in comparison to those with grades B or C (25.8 versus 17.5 mL, P =0.02). The method of bypass (direct or indirect) did not alter relative increases in CVR (8 versus 3.8 mL/100 g per minute, P =0.7). Conclusions: Acetazolamide-challenged arterial spin labeling noninvasively quantifies augmentation of CVR following surgery for Moyamoya disease and syndrome.

OBJECTIVE Microsurgical resection of arteriovenous malformations (AVMs) can be aided by staged treatment consisting of stereotactic radiosurgery followed by resection in a delayed fashion. This approach is particularly useful for high Spetzler-Martin (SM) grade lesions because radiosurgery can reduce flow through the AVM, downgrade the SM rating, and induce histopathological changes that additively render the AVM more manageable for resection. The authors present their 28-year experience in managing AVMs with adjunctive radiosurgery followed by resection. METHODS The authors retrospectively reviewed records of patients treated for cerebral AVMs at their institution between January 1990 and August 2019. All patients who underwent stereotactic radiosurgery (with or without embolization), followed by resection, were included in the study. Of 1245 patients, 95 met the eligibility criteria. Univariate and multivariate regression analyses were performed to assess relationships between key variables and clinical outcomes. RESULTS The majority of lesions treated (53.9%) were high grade (SM grade IV–V), 31.5% were intermediate (SM grade III), and 16.6% were low grade (SM grade I–II). Hemorrhage was the initial presenting sign in half of all patients (49.5%). Complete resection was achieved among 84% of patients, whereas 16% had partial resection, the majority of whom received additional radiosurgery. Modified Rankin Scale (mRS) scores of 0–2 were achieved in 79.8% of patients, and 20.2% had poor (mRS scores 3–6) outcomes. Improved (44.8%) or stable (19%) mRS scores were observed among 63.8% of patients, whereas 36.2% had a decline in mRS scores. This includes 22 patients (23.4%) with AVM hemorrhage and 6 deaths (6.7%) outside the perioperative period but prior to AVM obliteration. CONCLUSIONS Stereotactic radiosurgery is a useful adjunct in the presurgical management of cerebral AVMs. Multimodal therapy allowed for high rates of AVM obliteration and acceptable morbidity rates, despite the predominance of high-grade lesions in this series of patients.

Moyamoya disease (MMD) is characterized by progressive occlusion of the intracranial internal carotid arteries, leading to ischemic and hemorrhagic events. Significant clinical differences exist between ischemic and hemorrhagic MMD. To understand the molecular profiles in the cerebrospinal fluid (CSF) of MMD patients, we investigated 62 secreted factors in both MMD subtypes (ischemic and hemorrhagic) and examined their relationship with preoperative perfusion status, the extent of postoperative angiographic revascularization, and functional outcomes. Intraoperative CSF was collected from 32 control and 71 MMD patients (37 ischemic and 34 hemorrhagic). Multiplex Luminex assay analysis showed that 41 molecules were significantly elevated in both MMD subtypes when compared to controls, including platelet-derived growth factor-BB (PDGF-BB), plasminogen activator inhibitor 1 (PAI-1), and intercellular adhesion molecule 1 (ICAM1) (p

Introduction: Currently, no treatment exists to restore function in chronic stroke patients. Several prior intracerebral stem cell trials showed safety, but are not being further developed. Objective: NR1 is a human embryonic derived neural stem cell that improved motor-sensory function in rodent stroke models, and was expanded to produce GMP cryopreserved Cell Lots (P18). The aim is to assess the safety, tolerability and efficacy using intracerebral transplantation of NR1 cells in chronic stroke patients (NCT04631406). Methods: Inclusion Criteria: 18-75 yo; 6-60 months post-ischemic subcortical MCA stroke; mRS 3-4. Subjects are transplanted with NR1 (2.5M, 5M, 10M or 20M). Primary Outcomes: Adverse events 0-6 mos; Change in Fugl-Meyer (FM) motor score (maximum FM 100) compared to baseline at 6 months (≥10 points improvement considered “clinically meaningful”). Other outcomes: Barthel Index, NIHSS, Gait Speed test, mRS, MRI DTI, FLAIR, Resting State fMRI and [18F] FDG PET. Results: Six patients have been transplanted. Adverse events included headache and worsened speech, all resolving spontaneously. At 6 mos post-transplant: FM improved 15, 13 and 9 points in patients 1, 2 and 3 (all with faster gait); Barthel Index improved 5, 10 and 15 points. At 3 months FM improved 15 points (with faster gait) in patient 4. NIHSS improved 2 points in 2 patients and worsened 1 point in 1 patient. There was no change in mRS. All 6 patients demonstrated a new transient FLAIR signal in premotor cortex at d7, that resolved by 2 mos, which in prior studies was highly correlated with sustained neurologic recovery. An increase in regional homogeneity (ReHo) and fractional amplitude of low-frequency fluctuations (fALFFs) was observed in the sensorimotor network ipsilateral to the chronic infarction in patients with clinical improvement. Six additional patients are scheduled in the next 6 months. Conclusions: Intraparenchymal transplantation with NR1 cells in chronic stroke patients appears safe and well tolerated. Early results suggest improved motor function at 1-6 months post-implant.

OBJECTIVE There remains a paucity of literature on hypothalamic cavernous malformations (HCMs). Here, the authors present the largest series of HCMs to date and review the literature to gain additional insight into this rare disease subset. METHODS A prospectively managed database was retrospectively reviewed for patients diagnosed with symptomatic HCM and treated surgically between 1987 and 2019. Data gathered included demographics, presenting signs, radiological measurements, surgical approach, and postoperative events. Functional outcome was measured using the modified Rankin Scale (mRS) and Glasgow Outcome Scale–Extended (GOSE) pre- and postoperatively. A PRISMA guideline systematic review of HCM in the literature was performed. RESULTS Our cohort study consisted of 12 patients with symptomatic, and radiographically confirmed, HCM treated with microsurgery by the senior author (G.K.S.). An additional 16 surgically or conservatively managed patients were also identified from the literature, and the authors analyzed the data of all 28 patients (with 54% of patients being male; mean age 39 ± 16 years, range 10–68 years). Patients harboring HCMs most commonly presented with headache (16/28, 57%), short-term memory impairment (11/28, 39%), and gait disturbance (8/28, 32%). Radiographically, lesions most commonly involved the mammillary region (18/23, 78%), the tuberal/infundibulum region (13/23, 57%), and the preoptic/lamina terminalis region (12/23, 52%), with a mean diameter of 2.5 ± 1.4 cm (range 0.8–7 cm) at presentation. Acute hemorrhage was identified in 96% (23/24) of patients on presentation, with 96% (23/24) intraparenchymal and 29% (7/24) intraventricular. Of 24 patients who were managed surgically, gross-total resection (GTR) was achieved in 88% (21/24) of cases. There were no reports of perioperative infarction or mortality. With a mean follow-up period of 41 months (range 0.5–309 months), 77% (20/26) of patients experienced functional improvement, while 12% (3/26) had no change, and 12% (3/26) experienced increased disability. In our cohort of 12 patients, 83% (10/12) continued to report symptoms at the last follow-up (mean 4.8 years, range 0.1–25.7 years). However, there was a significant improvement in mRS score noted after surgery (mean 1.4 vs 3.1, p = 0.0026) and a trend toward improvement in GOSE score (mean 6.3 vs 5.1, p = 0.09). CONCLUSIONS Hemorrhage from HCMs can cause a symptomatic mass effect on adjacent eloquent structures. While patients are unlikely to be deficit free following surgery, GTR allows for functional improvement and reduces recurrent hemorrhage rates. Microsurgery remains a viable option for symptomatic HCMs in experienced hands.

OBJECTIVEReports on basal ganglia cavernous malformations (BGCMs) are rare. Here, the authors report on their experience in resecting these malformations to offer insight into this infrequent disease subtype.METHODSThe authors retrospectively reviewed a prospectively managed departmental database of all deep-seated cerebral cavernous malformations (CCMs) treated at Stanford between 1987 and 2019 and included for further analysis those with a radiographic diagnosis of BGCM. Moreover, a systematic literature review was undertaken using the PubMed and Web of Science databases.RESULTSThe departmental database search yielded 331 patients with deep-seated CCMs, 44 of whom had a BGCM (13.3%). Headache was the most common presenting sign (53.5%), followed by seizure (32.6%) and hemiparesis (27.9%). Lesion location involved the caudate nucleus in 21.4% of cases compared to 78.6% of cases within the lentiform nucleus. Caudate BGCMs were larger on presentation and were more likely to present to the ependymal surface (p < 0.001) with intraventricular hemorrhage and hydrocephalus (p = 0.005 and 0.007, respectively). Dizziness and diplopia were also more common with lesions involving the caudate. Because of their anatomical location, caudate BGCMs were preferentially treated via an interhemispheric approach and were less likely to be associated with worsening perioperative deficits than lentiform BGCMs (p = 0.006 and 0.045, respectively). Ten patients (25.6%) were clinically worse in the immediate postoperative period, 4 (10.2%) of whom continued to suffer permanent morbidity at the last follow-up. A long-term good outcome (modified Rankin Scale [mRS] score 0–1) was attained in 74.4% of cases compared to the 69.2% of patients who had presented with an mRS score 0–1. Relative to their presenting mRS score, 89.8% of patients had an improved or unchanged status at the last follow-up. The median postoperative follow-up was 11 months (range 1–252 months). Patient outcomes after resection did not differ among surgical approaches; however, patients presenting with hemiparesis and lesions involving the globus pallidus or posterior limb of the internal capsule were more likely to suffer neurological deficits during the immediate perioperative period. Patients who had undergone awake surgeries were more likely to suffer neurological decline at the early as well as the late follow-up. When adjusting for awake craniotomy as a potential confounder of lesion location, a BGCM involving the posterior limb was predictive of developing early postoperative deficits, but this finding did not persist at the long-term follow-up.CONCLUSIONSSurgery is a safe and effective treatment modality for managing BGCMs, with an estimated long-term permanent morbidity rate of around 10%.

Cerebrovascular reserve (CVR) reflects the capacity of cerebral blood flow (CBF) to change. Decreased CVR implies poor hemodynamics and is linked to a higher risk for stroke. Revascularization has been shown to improve CBF in patients with vasculopathy such as Moyamoya disease. Dynamic susceptibility contrast (DSC) can measure transit time to evaluate patients suspected of stroke. Arterial spin labeling (ASL) is a non-invasive technique for CBF, CVR, and arterial transit time (ATT) measurements. Here, we investigate the change in hemodynamics 4-12 months after extracranial-to-intracranial direct bypass in 52 Moyamoya patients using ASL with single and multiple post-labeling delays (PLD). Images were collected using ASL and DSC with acetazolamide. CVR, CBF, ATT, and time-to-maximum (Tmax) were measured in different flow territories. Results showed that hemodynamics improved significantly in regions affected by arterial occlusions after revascularization. CVR increased by 16 ± 11% (p 2 = 0.59, p

The therapeutic efficacy of stem cells transplanted into an ischaemic brain depends primarily on the responses of the neurovascular unit. Here, we report the development and applicability of a functional neurovascular unit on a microfluidic chip as a microphysiological model of ischaemic stroke that recapitulates the function of the blood-brain barrier as well as interactions between therapeutic stem cells and host cells (human brain microvascular endothelial cells, pericytes, astrocytes, microglia and neurons). We used the model to track the infiltration of a number of candidate stem cells and to characterize the expression levels of genes associated with post-stroke pathologies. We observed that each type of stem cell showed unique neurorestorative effects, primarily by supporting endogenous recovery rather than through direct cell replacement, and that the recovery of synaptic activities is correlated with the recovery of the structural and functional integrity of the neurovascular unit rather than with the regeneration of neurons.

This review captures recent advances in biological and translational research on stem cells. In particular, we discuss new discoveries and concepts regarding stem cell treatment of aging-related disorders. A myriad of stem cell sources exists, from hematopoietic to mesenchymal and neural cell lineages. We examine current applications of exogenous adult bone marrow-derived stem cells as an effective and safe transplantable cell source, as well as the use of electrical stimulation to promote endogenous neurogenesis for Parkinson's disease. We also explore the potential of transplanting exogenous umbilical cord blood cells and mobilizing host resident stem cells in vascular dementia and aging. In addition, we assess the ability of small molecules to recruit resident stem cells in Alzheimer's disease. Finally, we evaluate mechanisms of action recently implicated in stem cell therapy, such as the role of long non-coding RNAs, G-protein coupled receptor 5, and NeuroD1. Our goal is to provide a synopsis of recent milestones regarding the application of stem cells in aging.

Background Virtual reality (VR) allows for presurgical planning. Intraoperatively, augmented reality (AR) enables integration of segmented anatomic information with neuronavigation into the microsurgical scene to provide guidance without workflow disruption. Combining VR and AR solutions may help guide microsurgical technique to improve safety, efficiency, and ergonomics. Objective To describe a VR/AR platform that provides VR planning and intraoperative guidance via microscope ocular injection of a comprehensive AR overlay of patient-specific 360°/3D anatomic model aligned and synchronized with neuronavigation. Methods Custom 360° models from preoperative imaging of 49 patients were utilized for preoperative planning using a VR-based surgical rehearsal platform. Each model was imported to SyncAR, the platform's intraoperative counterpart, which was coregistered with Medtronic StealthStation S8 and Zeiss or Leica microscope. The model was injected into the microscope oculars and referenced throughout by adjusting overlay opacity. For anatomic shifts or misalignment, the overlay was reregistered via manual realignment with known landmarks. Results No SyncAR-related complications occurred. SyncAR contributed positively to the 3D understanding of patient-specific anatomy and ability to operate. Preoperative planning and intraoperative AR with 360° models allowed for more precise craniotomy planning and execution. SyncAR was useful for guiding dissection, identifying critical structures including hidden anatomy, understanding regional anatomy, and facilitating resection. Manual realignment was performed in 48/49 surgeries. Gross total resection was achieved in 34/40 surgeries. All aneurysm clipping and microvascular decompression procedures were completed without complications. Conclusion SyncAR combined with VR planning has potential to enhance surgical performance by providing critical information in a user-friendly, continuously available, heads-up display format.

Background/ImportanceDelayed cerebral ischemia (DCI) is the second-leading cause of death and disability in patients with aneurysmal subarachnoid hemorrhage (aSAH), and is associated with cerebral arterial vasospasm (CAV). Current treatments for CAV are expensive, invasive, and have limited efficacy. Cervical sympathetic block (CSB) is an underappreciated, but potentially highly effective therapy for CAV.ObjectiveTo provide a comprehensive review of the preclinical and human literature pertinent to CSB in the context of CAV.Evidence reviewThis study followed Preferred Reporting Items for Systematic Reviews and Meta-Analyses Extension for Scoping Reviews guidelines. We conducted a literature search using Embase, PubMed, Cochrane Database of Systematic Reviews, Cochrane Central Register of Controlled Trials, Scopus and Web of Science until February 2022, to identify abstracts, conference proceedings, and full-text papers pertinent to cervical sympathectomy and CAV in animal/adult patients.FindingsWe included six human and six experimental studies. Human studies were mostly prospective observational, except one retrospective and one randomized clinical trial, and used various imaging modalities to measure changes in arterial diameter after the block. Studies that used digital subtraction angiography showed an improvement in cerebral perfusion without change in vessel diameter. Transcranial Doppler studies found an approximately 15% statistically significant decrease in velocities consistent with arterial vasodilatation. Overall, the results suggest an increase in cerebral arterial diameter and neurological improvement in patients receiving a CSB. Animal studies demonstrate that sympathetic system ablation vasodilates cerebral vasculature and decreases the incidence of symptomatic vasospasm.ConclusionsThis scoping review suggests that CSB may be a viable option for treatment and prevention of CAV/DCI in patients with aSAH, although the included studies were heterogeneous, mostly observational, and with a small sample size. Further research is needed to standardize the technique and prove its effectiveness to treat patients suffering of CAV/DCI after aSAH.

OBJECTIVE The only effective treatment for ischemic moyamoya disease (iMMD) is cerebral revascularization by an extracranial to intracranial bypass. The preferred revascularization method remains controversial: direct versus indirect bypass. The purpose of this study was to test the hypothesis that method choice should be personalized based on angiographic, hemodynamic, and clinical characteristics to balance the risk of perioperative major stroke against treatment efficacy. METHODS Patients with iMMD were identified retrospectively from a prospectively maintained database. Those with mild to moderate internal carotid artery or M1 segment stenosis, preserved cerebrovascular reserve, intraoperative M4 segment anterograde flow ≥ 8 ml/min, or the absence of frequent and severe transient ischemic attacks (TIAs) or stroke had been assigned to indirect bypass. The criteria for direct bypass were severe ICA or M1 segment stenosis or occlusion, impaired cerebrovascular reserve or steal phenomenon, intraoperative M4 segment retrograde flow or anterograde flow < 8 ml/min, and the presence of frequent and severe TIAs or clinical strokes. The primary study endpoint was MRI-confirmed symptomatic stroke ≤ 7 days postoperatively resulting in a decline in the modified Rankin Scale (mRS) score from preoperatively to 6 months postoperatively. As a secondary endpoint, the authors assessed 6-month postoperative DSA-demonstrated revascularization, which was classified as < 1/3, 1/3–2/3, or > 2/3 of the middle cerebral artery territory. RESULTS One hundred thirty-eight patients with iMMD affecting 195 hemispheres revascularized in the period from March 2016 to June 2018 were included in this analysis. One hundred thirty-three hemispheres were revascularized with direct bypass and 62 with indirect bypass. The perioperative stroke rate was 4.7% and 6.8% in the direct and indirect groups, respectively (p = 0.36). Degree of revascularization was higher in the direct bypass group (p = 0.03). The proportion of patients improving to an mRS score 0–1 (from preoperatively to 6 months postoperatively) tended to be higher in the direct bypass group, although the difference between the two bypass groups was not statistically significant (p = 0.27). CONCLUSIONS The selective use of an indirect bypass procedure for iMMD did not decrease the perioperative stroke rate. Direct bypass provided a significantly higher degree of revascularization. The authors conclude that direct bypass is the treatment of choice for iMMD.

The field of data science has great potential to address critical questions relevant for academic medical centers. Data science initiatives are consequently being established within academic medicine. At the cornerstone of such initiatives are scientists who practice data science. These scientists include biostatisticians, clinical informaticians, database and software developers, computational scientists, and computational biologists. Too often, however, those involved in the practice of data science are viewed by academic leadership as providing a noncomplex service to facilitate research and further the careers of other academic faculty. The authors contend that the success of data science initiatives relies heavily on the understanding that the practice of data science is a critical intellectual contribution to the overall science conducted at an academic medical center. Further, careful thought by academic leadership is needed for allocation of resources devoted to the practice of data science. At the Stanford University School of Medicine, the authors have developed an innovative model for a data science collaboratory based on 4 fundamental elements: an emphasis on collaboration over consultation; a subscription-based funding mechanism that reflects commitment by key partners; an investment in the career development of faculty who practice data science; and a strong educational component for data science members in team science and for clinical and translational investigators in data science. As data science becomes increasingly essential to learning health systems, centers that specialize in the practice of data science are a critical component of the research infrastructure and intellectual environment of academic medical centers.

Background Aneurysmal subarachnoid hemorrhage results in significant mortality and disability, which is worsened by the development of delayed cerebral ischemia. Tests to identify patients with delayed cerebral ischemia prospectively are of high interest. Objective We created a machine learning system based on clinical variables to predict delayed cerebral ischemia in aneurysmal subarachnoid hemorrhage patients. We also determined which variables have the most impact on delayed cerebral ischemia prediction using SHapley Additive exPlanations method. Methods 500 aneurysmal subarachnoid hemorrhage patients were identified and 369 met inclusion criteria: 70 patients developed delayed cerebral ischemia (delayed cerebral ischemia+) and 299 did not (delayed cerebral ischemia−). The algorithm was trained based upon age, sex, hypertension (HTN), diabetes, hyperlipidemia, congestive heart failure, coronary artery disease, smoking history, family history of aneurysm, Fisher Grade, Hunt and Hess score, and external ventricular drain placement. Random Forest was selected for this project, and prediction outcome of the algorithm was delayed cerebral ischemia+. SHapley Additive exPlanations was used to visualize each feature's contribution to the model prediction. Results The Random Forest machine learning algorithm predicted delayed cerebral ischemia: accuracy 80.65% (95% CI: 72.62–88.68), area under the curve 0.780 (95% CI: 0.696–0.864), sensitivity 12.5% (95% CI: −3.7 to 28.7), specificity 94.81% (95% CI: 89.85–99.77), PPV 33.3% (95% CI: −4.39 to 71.05), and NPV 84.1% (95% CI: 76.38–91.82). SHapley Additive exPlanations value demonstrated Age, external ventricular drain placement, Fisher Grade, and Hunt and Hess score, and HTN had the highest predictive values for delayed cerebral ischemia. Lower age, absence of hypertension, higher Hunt and Hess score, higher Fisher Grade, and external ventricular drain placement increased risk of delayed cerebral ischemia. Conclusion Machine learning models based upon clinical variables predict delayed cerebral ischemia with high specificity and good accuracy.

Cerebrovascular reactivity (CVR) reflects the CBF change to meet different physiological demands. The reference CVR technique is PET imaging with vasodilators but is inaccessible to most patients. DSC can measure transit time to evaluate patients suspected of stroke, but the use of gadolinium may cause side-effects. Arterial spin labeling (ASL) is a non-invasive MRI technique for CBF measurements. Here, we investigate the effectiveness of ASL with single and multiple post labeling delays (PLD) to replace PET and DSC for CVR and transit time mapping in 26 Moyamoya patients. Images were collected using simultaneous PET/MRI with acetazolamide. CVR, CBF, arterial transit time (ATT), and time-to-maximum (Tmax) were measured in different flow territories. Results showed that CVR was lower in occluded regions than normal regions (by 68 ± 12%, 52 ± 5%, and 56 ± 9%, for PET, single- and multi-PLD PCASL, respectively, all p 2 > 0.35, p

Introduction Dural arteriovenous fistulae (DAVF) are vascular lesions with arteriovenous shunting that may be treated with surgical obliteration or endovascular embolization. Some DAVF, such as anterior cranial fossa DAVF (AC-DAVF) derive their arterial supply from ophthalmic artery branches in nearly all cases, and trans-arterial embolization carries a risk of vision loss. We determined the efficacy and safety of trans-ophthalmic artery embolization of DAVF. Materials and methods We performed a retrospective cohort study of all patients with DAVF treated by trans-ophthalmic artery embolization from 2012 to 2020. Primary outcome was angiographic cure of the DAVF. Secondary outcomes included vision loss, visual impairment, orbital cranial nerve injury, stroke, modified Rankin Scale at 90-days, and mortality. Results 12 patients met inclusion criteria (9 males; 3 females). 10 patients had AC-DAVF. Patient age was 59.7 ± 9.5 (mean ± SD) years. Patients presented with intracranial hemorrhage (4 patients), headache (4 patients), amaurosis fugax (1 patients), or were incidentally discovered (2 patients). DAVF Cognard grades were: II (1 patient), III (6 patients), and IV (5 patients). DAVF were embolized with Onyx (10 patients), nBCA glue (1 patient), and a combination of coils and Onyx (1 patient). DAVF cure was achieved in 11 patients (92%). No patients experienced vision loss, death, or permanent disability. One patient experienced a minor complication of blurry vision attributed to posterior ischemic optic neuropathy. 90-day mRS was 0 (10 patients) and 1 (2 patients). Conclusions Trans-ophthalmic artery embolization is an effective and safe treatment for DAVF.

OBJECTIVECavernous malformations (CMs) are commonly treated cerebrovascular anomalies in the pediatric population; however, the data on radiographic recurrence of pediatric CMs after surgery are limited. The authors aimed to study the clinical presentation, outcomes, and recurrence rate following surgery for a large cohort of CMs in children.METHODSPediatric patients (≤ 18 years old) who had a CM resected at a single institution were identified and retrospectively reviewed. Fisher’s exact test of independence was used to assess differences in categorical variables. Survival curves were evaluated using the Mantel-Cox method.RESULTSFifty-three patients aged 3 months to 18 years underwent resection of 74 symptomatic CMs between 1996 and 2018 at a single institution. The median length of follow-up was 5.65 years. Patients most commonly presented with seizures (45.3%, n = 24) and the majority of CMs were cortical (58.0%, n = 43). Acute radiographic hemorrhage was common at presentation (64.2%, n = 34). Forty-two percent (n = 22) of patients presented with multiple CMs, and they were more likely to develop de novo lesions (71%) compared to patients presenting with a single CM (3.4%). Both radiographic hemorrhage and multiple CMs were independently prognostic for a higher risk of the patient requiring subsequent surgery. Fifty percent (n = 6) of the 12 patients with both risk factors required additional surgery within 2.5 years of initial surgery compared to none of the patients with neither risk factor (n = 9).CONCLUSIONSPatients with either acute radiographic hemorrhage or multiple CMs are at higher risk for subsequent surgery and require long-term MRI surveillance. In contrast, patients with a single CM are unlikely to require additional surgery and may require less frequent routine imaging.

Post-stroke optogenetic stimulation has been shown to enhance neurovascular coupling and functional recovery. Neuronal nitric oxide synthase (nNOS) has been implicated as a key regulator of the neurovascular response in acute stroke; however, its role in subacute recovery remains unclear. We investigated the expression of nNOS in stroke mice undergoing optogenetic stimulation of the contralesional lateral cerebellar nucleus (cLCN). We also examined the effects of nNOS inhibition on functional recovery using a pharmacological inhibitor targeting nNOS. Optogenetically stimulated stroke mice demonstrated significant improvement on the horizontal rotating beam task at post-stroke days 10 and 14. nNOS mRNA and protein expression was significantly and selectively decreased in the contralesional primary motor cortex (cM1) of cLCN-stimulated mice. The nNOS expression in cM1 was negatively correlated with improved recovery. nNOS inhibitor (ARL 17477)-treated stroke mice exhibited a significant functional improvement in speed at post-stroke day 10, when compared to stroke mice receiving vehicle (saline) only. Our results show that optogenetic stimulation of cLCN and systemic nNOS inhibition both produce functional benefits after stroke, and suggest that nNOS may play a maladaptive role in post-stroke recovery.

BackgroundPrecise delivery of liquid embolic agents (LEAs) remains a challenge in the endovascular treatment of dural arteriovenous fistulae (dAVFs) and cerebral arteriovenous malformations (cAVMs). Despite significant advances in the past decade, LEA reflux and catheter navigability remain shortcomings of current endovascular technology, particularly in small and tortuous arteries. The Scepter Mini dual-lumen balloon microcatheter aims to address these issues by decreasing the distal catheter profile (1.6 French) while allowing for a small (2.2 mm diameter) balloon at its tip.MethodsWe report our initial experience with the Scepter Mini in two patients with anterior cranial fossa dAVFs that were treated with transophthalmic artery embolization.ResultsIn both patients, the Scepter Mini catheter was able to be safely advanced into the distal ophthalmic artery close to the fistula site, and several centimeters past the origins of the central retinal and posterior ciliary arteries. A single Onyx injection without any reflux resulted in angiographic cure of the dAVF in both cases, and neither patient suffered any vision loss.ConclusionsThese initial experiences suggest that the Scepter Mini represents a significant advance in the endovascular treatment of dAVFs and cAVMs and will allow for safer and more efficacious delivery of LEAs into smaller and more distal arteries while diminishing the risk of LEA reflux.

Background and purpose Brain arteriovenous malformation (AVM) treatment by stereotactic radiosurgery (SRS) is effective, but AVM obliteration following SRS may take two years or longer. MRI with arterial-spin labeling (ASL) may detect brain AVMs with high sensitivity. We determined whether brain MRI with ASL may accurately detect residual AVM following SRS treatment. Materials and methods We performed a retrospective cohort study of patients who underwent brain AVM evaluation by DSA between June 2010 and June 2015. Inclusion criteria were: (1) AVM treatment by SRS, (2) follow-up MRI with ASL at least 30 months after SRS, (3) DSA within 3 months of the follow-up MRI with ASL, and (4) no intervening AVM treatment between the MRI and DSA. Four neuroradiologists blindly and independently reviewed follow-up MRIs. Primary outcome measure was residual AVM indicated by abnormal venous ASL signal. Results 15 patients (12 females, mean age 29 years) met inclusion criteria. There were three posterior fossa AVMs and 12 supratentorial AVMs. Spetzler–Martin (SM) Grades were: SM1 (8%), SM2 (33%), SM3 (17%), SM4 (25%), and SM5 (17%). DSA demonstrated residual AVM in 10 patients. The pooled sensitivity, specificity, positive predictive value, and negative predictive value of venous ASL signal for predicting residual AVM were 100% (95% CI: 0.9-1.0), 95% (95% CI: 0.7–1.0), 98% (95% CI: 0.9–1.0), and 100% (95% CI: 0.8–1.0), respectively. High inter-reader agreement as found by Fleiss’ Kappa analysis (k = 0.92; 95% CI: 0.8–1.0; P Conclusions ASL is highly sensitive and specific in the detection of residual cerebral AVM following SRS treatment.

OBJECTIVE The post-bypass stroke risk factors and long-term outcomes of moyamoya patients are not well documented. Therefore, the authors studied 30-day stroke risks and patients’ long-term physical, functional, and social well-being. METHODS This was a single-institution combined moyamoya disease (MMD) database interrogation and questionnaire study. From 1991 to 2014, 1250 revascularization procedures (1118 direct bypasses, 132 indirect bypasses) were performed in 769 patients. Completed questionnaires were received from and available for analysis on 391 patients, and 6-month follow-up data were available for 96.4% (741/769) of the patients. RESULTS The patients consisted of 548 females and 221 males, with a mean age of 32 years (range 1–69 years). Three hundred fifty-eight bypasses were performed in 205 pediatric patients (73% direct bypasses), and 892 revascularizations were performed in 564 adults (96% direct bypasses). Fifty-two patients (6.8%) developed major strokes with a worsening modified Rankin Scale (mRS) score within 30 days postoperatively. The 30-day major stroke risk was 5.3% (41/769) and 2.6% (12/467) after the first and second bypasses, respectively. Logistic regression analysis revealed that older age, modified MRI (mMRI) score, and hemodynamic reserve (HDR) score are clearly associated with higher postoperative stroke risks. Over a mean follow-up of 7.3 years (range 0.5–26 years), the long-term stroke risk among 741 patients was 0.6% per patient-year; 75% of these patients had excellent outcomes (mRS score 0–1). The long-term outcome questionnaire study showed that 84% (234/277) of patients reported resolution or improvement in their preoperative headache, 83% (325/391) remained employed or in school, and 87% (303/348) were self-caring. CONCLUSIONS In this large, single-center surgical series, most of the adult and pediatric patients had direct revascularization, with a 4.2% per-bypass-procedure (6.8% per patient) 30-day major stroke risk and a 0.6% per-patient-year long-term stroke risk. The authors identified various risk factors that are highly correlated with postoperative morbidity (age, mMRI score, and HDR score) and are involved in ongoing work to develop the predictive modeling for future patient selection and treatment.

OBJECTIVE The primary objective of this study was to evaluate the safety of 3 escalating doses of oligodendrocyte progenitor cells (LCTOPC1; previously known as GRNOPC1 and AST-OPC1) administered at a single time point between 21 and 42 days postinjury to participants with subacute cervical spinal cord injuries (SCIs). The secondary objective was to evaluate changes in neurological function following administration of LCTOPC1. METHODS This study was designed as an open-label, dose-escalation, multicenter clinical trial. Twenty-five participants with C4–7 American Spinal Injury Association Impairment Scale grade A or B injuries received a single dose of either 2 × 106, 1 × 107, or 2 × 107 LCTOPC1 delivered via intraparenchymal injection into the spinal cord at the site of injury using a custom-designed syringe positioning device. Low-dose tacrolimus was administered until day 60. Outcome measures included adverse event (AE) monitoring and neurological function as measured by the International Standards for Neurological Classification of Spinal Cord Injury. RESULTS All 25 participants experienced at least one AE, with a total of 534 AEs (32 study-related vs 502 study-unrelated anticipated complications of SCI) reported at the completion of 1-year follow-up. There were 29 serious AEs reported. Two grade 3 serious AEs (CSF leak in one participant and a bacterial infection in another) were considered related to the injection procedure and to immunosuppression with tacrolimus, respectively. The CSF leakage resolved with sequelae, including self-limited altered mental status, and the infection resolved with antibiotic therapy. For all participants, MRI scans demonstrated no evidence of an enlarging mass, spinal cord damage related to the injection procedure, inflammatory lesions in the spinal cord, or masses in the ventricular system. At 1-year follow-up, 21/22 (96%) of the intention-to-treat group recovered one or more levels of neurological function on at least one side of their body, and 7/22 (32%) recovered two or more levels of neurological function on at least one side of their body. CONCLUSIONS LCTOPC1 can be safely administered to participants in the subacute period after cervical SCI. The injection procedure, low-dose temporary immunosuppression regimen, and LCTOPC1 were well tolerated. The safety and neurological function data support further investigation to determine the efficacy of LCTOPC1 in the treatment of SCI. Clinical trial registration no.: NCT02302157 (ClinicalTrials.gov)

Introduction: Loss of neuronal activity after stroke can impact many activity-dependent processes including oligodendrocyte maturation and myelination. The cortico-thalamic circuit is particularly disrupted after cortical stroke, resulting in secondary axonal degeneration in the thalamus. This secondary thalamic injury is associated with worsened functional outcomes. Increasing neuronal activity by optogenetic stimulation promotes oligodendrogenesis and myelination in normal conditions. In this study, we use optogenetic stimulation to selectively re-activate the cortico-thalamic circuit after stroke and examine its effects on oligodendrocytes in the degenerative thalamus. Methods: C57BL6 male mice (6-8 weeks old) were injected AAV1-CaMKIIa-hChR2 virus in the ipsilesional somatosensory cortex and implanted an optic fiber in the ipsilesional thalamus. After six weeks, the left middle cerebral artery was permanently occluded to generate infarct in iS1. Stimulated mice were given daily optogenetic stimulations between Post-stroke Day (PD) 4 to 14. Brain sections were immunostained to detect primary cortical injury and secondary thalamic injury (NeuN), and neuroinflammation (CD68) and oligodendrogenesis (Olig2 and CC1) in the thalamus. Results: ChR2 is specifically expressed in the somatosensory cortico-thalamic tract. Neuronal loss and robust neuroinflammation were observed in iTH after stroke, but there was no significant difference between non-stimulated and stimulated mice. However, stimulated mice exhibited 5.5 times increase in the numbers of mature oligodendrocytes (Olig2 + CC1 + , p=0.02, n=5/group), and 5.4 times increase in the numbers of oligodendrocyte progenitor cells (Olig2 + , p=0.03) in the degenerative thalamus. Conclusion: Our data demonstrate that selective re-activation of the cortical-thalamic circuits promoted oligodendrogenesis in the secondary degenerative thalamus after stroke. As the secondary thalamic injury allows an extended treatment window, targeting secondary injury is a promising approach to improve stroke recovery. Current studies are testing the effects of cortico-thalamic circuit stimulation in myelination in the degenerative thalamus and functional outcome after stroke.

3D histology, slice-based connectivity atlases, and diffusion MRI are common techniques to map brain wiring. While there are many modality-specific tools to process these data, there is a lack of integration across modalities. We develop an automated resource that combines histologically cleared volumes with connectivity atlases and MRI, enabling the analysis of histological features across multiple fiber tracts and networks, and their correlation with in-vivo biomarkers. We apply our pipeline in a murine stroke model, demonstrating not only strong correspondence between MRI abnormalities and CLARITY-tissue staining, but also uncovering acute cellular effects in areas connected to the ischemic core. We provide improved maps of connectivity by quantifying projection terminals from CLARITY viral injections, and integrate diffusion MRI with CLARITY viral tracing to compare connectivity maps across scales. Finally, we demonstrate tract-level histological changes of stroke through this multimodal integration. This resource can propel investigations of network alterations underlying neurological disorders., Many approaches exist to process data from individual imaging modalities, but integrating them is challenging. The authors develop an automated resource that enables co-registered network- and tract-level analysis of macroscopic in-vivo imaging and microscopic imaging of cleared tissue.