Impact of socioeconomics and race on clinical follow-up and trial enrollment and adherence in cerebral cavernous malformation.

OBJECTIVES: Cerebral cavernous malformation (CCM) affects more than a million Americans but advanced care for symptomatic lesions and access to research studies is largely limited to referral academic centers MATERIALS AND METHODS: A cohort of CCM patients screened for research studies at an accredited center of excellence for CCM was analyzed. Demographics, lesion location, history of hemorrhage, insurance type and area of deprivation index (ADI) were collected. Primary outcomes were clinical follow-up within a year from initial evaluation, and enrollment and adherence in clinical trials among eligible subjects RESULTS: A majority (52.8%) of CCM patients evaluated had a high socioeconomic status (SES) (ADI 1-3), and only 11.5% were African American. Patients who had a symptomatic bleed were more likely to follow-up (p=0.01), and those with brainstem lesion were more likely to enroll/adhere in a clinical trial (p=0.02). Rates of clinical follow-up were similar across different ADI groups, insurance coverage and race. Patients who were uninsured/self-paying, and African Americans were more likely to decline/drop from clinical trials (OR 2.4, 95% CI 0.46-10.20 and OR 2.2, 95% CI 0.33-10.75, respectively), but differences were not statistically significant CONCLUSIONS: Access of disadvantaged patients to center of excellence care and research remains limited despite geographic proximity to their community. Patients with lower SES and African Americans are as likely to follow-up clinically, but there were trends of differences in enrollment/adherence in clinical trials. Mitigation efforts should target systemic causes of low access to specialized care among uninsured and African American patients.

Overview of cerebral cavernous malformations: comparison of treatment approaches.

OBJECTIVES: The comparison of treatment efficacy for cerebral cavernous malformations (CCMs) has not yet been well researched. DESIGN: PubMed, Cochrane Library, Science Direct, ISI Web of Science, Embase and additional sources were searched to identify cohort studies about the treatment of CCMs published between 1990 and 2020. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines were followed; the Newcastle-Ottawa Scale was used to assess the risk of bias and to evaluate limitations based on selection/outcome biases. The cumulative incidences with 95% CIs were calculated using the random effects model. The models of Poisson distribution were applied to evaluate risk factors of poorer treatment outcome by calculating rate ratios within 100 person-years with 95% CIs. RESULTS: A total of 100 cohorts yielding 8994 patients treated for CCMs within 41 098 person-years of follow-up were analysed. The efficacy of ensuring the prevention of haemorrhage was 97% in surgical, 86% in radiosurgical and 77% in the conservative treatment. The lowest mortality (1%) was after radiosurgery, and the highest persistent morbidity (22%) was in natural history series. Deep-seated and brainstem CCMs were associated with higher bleeding rates. Lobar localisation was a protective factor in all analyses. Patients with history of previous haemorrhage were exposed to higher risk of rebleeding. Male gender was a protective factor associated with lower risk of post-treatment haemorrhage. CONCLUSIONS: Surgical resection of CCM is effective in ensuring the prevention of haemorrhage with acceptable morbidity and mortality, but conservative and radiosurgical management is a justified treatment alternative. Brainstem and deep-seated CCMs are predominantly associated with higher haemorrhage rates.

Outcome in Patients with Spinal Cavernomas Presenting with Symptoms Due to Mass Effect and/or Hemorrhage: Conservative versus Surgical Management: Meta-analysis of Direct Comparison of Approach-Related Complications.

OBJECTIVE: We sought to examine the conservative treatment of symptomatic spinal cavernomas and evaluate the efficacy and safety of surgical management of spinal cord cavernous malformations. METHODS: This meta-analysis included articles comparing outcomes of conservative treatment and surgical management of spinal cavernomas, published in the full-text form (from 2000 to June 31, 2020). Collected variables included first author name, country, covered study period, publication year, the total number of patients and at follow-up, bleeding, motor weakness, pain, bladder and/or bowel dysfunction neurologic improvement or deterioration after discharge, and the need for reintervention after subtotal surgical resection or hemorrhage. RESULTS: After the initial searching and applying all exclusion and inclusion criteria, there were 9 articles left in the final article pool. The total number of patients was 396 with 264 (66.6%) undergoing surgical resection and 132 (33.4%) electing conservative management. Regarding motor weakness, bladder/bowel dysfunction, deterioration, and reintervention, the final results demonstrated no potential significant difference between the 2 groups. In regard to the subgroup of patients with bleeding, improvement, and pain, the results of the analysis showed a statistically significant difference between the 2 groups. CONCLUSIONS: Patients who have experienced a hemorrhagic episode should consider surgical intervention, which decreases the risk of recurrent hemorrhage and further neurologic deterioration. In addition, surgical decompression obtained by resection of the hemorrhage and cavernoma seems to lead to slight neurologic improvement in some patients. In nonhemorrhagic cavernomas, conservative treatment might be optimal due to surgery-related morbidity risks.

Mortality in Patients with Brainstem Cavernous Malformations.

OBJECTIVE: Brainstem cavernous malformations (BSCM)-associated mortality has been reported up to 20% in patients managed conservatively, whereas postoperative mortality rates range from 0 to 1.9%. Our aim was to analyze the actual risk and causes of BSCM-associated mortality in patients managed conservatively and surgically based on our own patient cohort and a systematic literature review. METHODS: Observational, retrospective single-center study encompassing all patients with BSCM that presented to our institution between 2006 and 2018. In addition, a systematic review was performed on all studies encompassing patients with BSCM managed conservatively and surgically. RESULTS: Of 118 patients, 54 were treated conservatively (961.0 person years follow-up in total). No BSCM-associated mortality was observed in our conservatively as well as surgically managed patient cohort. Our systematic literature review and analysis revealed an overall BSCM-associated mortality rate of 2.3% (95% CI: 1.6-3.3) in 22 studies comprising 1,251 patients managed conservatively and of 1.3% (95% CI: 0.9-1.7) in 99 studies comprising 3,275 patients with BSCM treated surgically. CONCLUSION: The BSCM-associated mortality rate in patients managed conservatively is almost as low as in patients treated surgically and much lower than in frequently cited reports, most probably due to the good selection nowadays in regard to surgery.

Cerebral Cavernous Malformation: From Mechanism to Therapy.

Cerebral cavernous malformations are acquired vascular anomalies that constitute a common cause of central nervous system hemorrhage and stroke. The past 2 decades have seen a remarkable increase in our understanding of the pathogenesis of this vascular disease. This new knowledge spans genetic causes of sporadic and familial forms of the disease, molecular signaling changes in vascular endothelial cells that underlie the disease, unexpectedly strong environmental effects on disease pathogenesis, and drivers of disease end points such as hemorrhage. These novel insights are the integrated product of human clinical studies, human genetic studies, studies in mouse and zebrafish genetic models, and basic molecular and cellular studies. This review addresses the genetic and molecular underpinnings of cerebral cavernous malformation disease, the mechanisms that lead to lesion hemorrhage, and emerging biomarkers and therapies for clinical treatment of cerebral cavernous malformation disease. It may also serve as an example for how focused basic and clinical investigation and emerging technologies can rapidly unravel a complex disease mechanism.

Neurological outcomes of untreated brainstem cavernous malformations in a prospective observational cohort and literature review.

BACKGROUND: Haemorrhages of brainstem cavernous malformations (CMs) can lead to neurological deficits, the natural history of which is uncertain. The study aimed to evaluate the neurological outcomes of untreated brainstem CMs and to identify the adverse factors associated with worsened outcomes. METHODS: From 2009 to 2015, 698 patients (321 women) with brainstem CMs were entered into the prospective cohort after excluding patients lost to follow-up (n=43). All patients were registered, clinical data were collected and scheduled follow-up was performed. RESULTS: After a median follow-up of 60.9 months, prospective haemorrhages occurred in 167 patients (23.9%). The mean modified Rankin Scale scores at enrolment and at censoring time were 1.6 and 1.2. Neurological status was improved, unchanged and worsened in 334 (47.9%), 293 (42.0%) and 71 (10.2%) patients, respectively; 233 (33.4%) recovered to normal levels. Lesions crossing the axial midpoint (relative risk (RR) 2.325, p=0.003) and developmental venous anomaly (DVA) (RR 1.776, p=0.036) were independently significantly related to worsened outcomes. The percentage of worsened outcomes was 5.3% (18 of 337) in low-risk patients (neither DVA nor crossing the axial point) and increased to 26.0% (13 of 50) in high-risk patients (with both DVA and crossing the axial point). The percentage of worsened outcomes significantly increased as the number of prospective haemorrhages increased (from 1.5% (8 of 531, if 0 prospective ictus) to 37.5% (48 of 128, if 1 ictus) and 38.5% (15 of 39, if >1 ictus)). CONCLUSIONS: The neurological outcomes of untreated brainstem CMs were improved/unchanged in majority of patients (89.8%) with a fatality rate of 1.7% in our cohort, which seemed to be favourable. Radiological features significantly predicted worsened outcomes. Our results provide evidence for clinical consultation and individualised treatment. The referral bias of our cohort was underlined.

Towards precision nanomedicine for cerebrovascular diseases with emphasis on Cerebral Cavernous Malformation (CCM).

Introduction: Cerebrovascular diseases encompass various disorders of the brain vasculature, such as ischemic/hemorrhagic strokes, aneurysms, and vascular malformations, also affecting the central nervous system leading to a large variety of transient or permanent neurological disorders. They represent major causes of mortality and long-term disability worldwide, and some of them can be inherited, including Cerebral Cavernous Malformation (CCM), an autosomal dominant cerebrovascular disease linked to mutations in CCM1/KRIT1, CCM2, or CCM3/PDCD10 genes.Areas covered: Besides marked clinical and etiological heterogeneity, some commonalities are emerging among distinct cerebrovascular diseases, including key pathogenetic roles of oxidative stress and inflammation, which are increasingly recognized as major disease hallmarks and therapeutic targets. This review provides a comprehensive overview of the different clinical features and common pathogenetic determinants of cerebrovascular diseases, highlighting major challenges, including the pressing need for new diagnostic and therapeutic strategies, and focusing on emerging innovative features and promising benefits of nanomedicine strategies for early detection and targeted treatment of such diseases.Expert opinion: Specifically, we describe and discuss the multiple physico-chemical features and unique biological advantages of nanosystems, including nanodiagnostics, nanotherapeutics, and nanotheranostics, that may help improving diagnosis and treatment of cerebrovascular diseases and neurological comorbidities, with an emphasis on CCM disease.

Pediatric Cerebral Cavernous Malformations.

Cerebral cavernous malformations are the second most common vascular malformations in the central nervous system, and over one-third are found in children. Lesions may be solitary or multiple, be discovered incidentally, be sporadic, or be secondary to familial cavernomatosis or radiation therapy. Children may present with focal seizures, intracranial hemorrhage, or focal neurological deficits without radiological evidence of recent hemorrhage. We present several children with cerebral cavernous malformations and explore the challenges of their diagnosis in children, their key imaging features, the role of follow-up imaging, and their subsequent management including stereotactic radiosurgery and microsurgical resection. Individual patient risk stratification is advocated for all affected children and their families.

Signalling through cerebral cavernous malformation protein networks.

Cerebral cavernous malformations (CCMs) are neurovascular abnormalities characterized by thin, leaky blood vessels resulting in lesions that predispose to haemorrhages, stroke, epilepsy and focal neurological deficits. CCMs arise due to loss-of-function mutations in genes encoding one of three CCM complex proteins, KRIT1, CCM2 or CCM3. These widely expressed, multi-functional adaptor proteins can assemble into a CCM protein complex and (either alone or in complex) modulate signalling pathways that influence cell adhesion, cell contractility, cytoskeletal reorganization and gene expression. Recent advances, including analysis of the structures and interactions of CCM proteins, have allowed substantial progress towards understanding the molecular bases for CCM protein function and how their disruption leads to disease. Here, we review current knowledge of CCM protein signalling with a focus on three pathways which have generated the most interest-the RhoA-ROCK, MEKK3-MEK5-ERK5-KLF2/4 and cell junctional signalling pathways-but also consider ICAP1-ß1 integrin and cdc42 signalling. We discuss emerging links between these pathways and the processes that drive disease pathology and highlight important open questions-key among them is the role of subcellular localization in the control of CCM protein activity.

Cerebral Cavernous Malformation: What a Practicing Clinician Should Know.

Cavernous malformations (CMs) are angiographically occult, low-flow vascular malformations of the central nervous system. They are acquired lesions, with approximately 80% of patients having the sporadic form and 20% the familial form of the disease. The lesions may also develop years after radiotherapy. At the microscopic level, they consist of endothelium-lined cavities (or "caverns") containing blood of different ages. The endothelium proliferates abnormally, and tight junctions are absent or dysfunctional, resulting in leakiness of the endothelium and clinical manifestations in some patients. Cavernous malformations can be an incidental finding or can present with focal neurologic deficits, seizures, or headache, with or without associated hemorrhage. Management of the CM lesion requires knowledge of the natural history of the disease compared with the risk of surgical intervention. Surgery is often considered for symptomatic patients with lesions in a noneloquent location. Medical management is warranted for symptoms related to the CM. Research aimed at understanding the genes and signaling pathways related to CMs have provided potential drug targets, and clinical trials are underway to determine whether medications reduce the risk of future bleeding without surgery or modify the disease course. In addition, recent epidemiologic data have aided practitioners in determining how to treat comorbid conditions in patients with a potentially hemorrhagic lesion. This review provides an overview of the epidemiology, presentation, and clinical management of CMs.

From Genes and Mechanisms to Molecular-Targeted Therapies: The Long Climb to the Cure of Cerebral Cavernous Malformation (CCM) Disease.

Cerebral cavernous malformation (CCM) is a rare cerebrovascular disorder of genetic origin consisting of closely clustered, abnormally dilated and leaky capillaries (CCM lesions), which occur predominantly in the central nervous system. CCM lesions can be single or multiple and may result in severe clinical symptoms, including focal neurological deficits, seizures, and intracerebral hemorrhage. Early human genetic studies demonstrated that CCM disease is linked to three chromosomal loci and can be inherited as autosomal dominant condition with incomplete penetrance and highly variable expressivity, eventually leading to the identification of three disease genes, CCM1/KRIT1, CCM2, and CCM3/PDCD10, which encode for structurally unrelated intracellular proteins that lack catalytic domains. Biochemical, molecular, and cellular studies then showed that these proteins are involved in endothelial cell-cell junction and blood-brain barrier stability maintenance through the regulation of major cellular structures and mechanisms, including endothelial cell-cell and cell-matrix adhesion, actin cytoskeleton dynamics, autophagy, and endothelial-to-mesenchymal transition, suggesting that they act as pleiotropic regulators of cellular homeostasis, and opening novel therapeutic perspectives. Indeed, accumulated evidence in cellular and animal models has eventually revealed that the emerged pleiotropic functions of CCM proteins are mainly due to their ability to modulate redox-sensitive pathways and mechanisms involved in adaptive responses to oxidative stress and inflammation, thus contributing to the preservation of cellular homeostasis and stress defenses.In this introductory review, we present a general overview of 20 years of amazing progress in the identification of genetic culprits and molecular mechanisms underlying CCM disease pathogenesis, and the development of targeted therapeutic strategies.

Stereotactic laser interstitial thermal therapy for brainstem cavernous malformations: two preliminary cases.

Brainstem cavernous malformations (CMs) often have high hemorrhage rates and significant posthemorrhage morbidity. The authors present two cases in which magnetic resonance thermography-guided laser interstitial therapy was used for treatment of pontine CMs after recurrent hemorrhage. Both patients showed significant symptomatic improvement and were hemorrhage-free at 12- and 6-month follow-up, respectively. Each had radiographic evidence of lesion involution on serial follow-up imaging. These early results demonstrate this treatment modality may be technically safe; however, larger case numbers and longer follow-up are needed to demonstrate efficacy.

Subclinical imaging changes in cerebral cavernous angiomas during prospective surveillance.

OBJECTIVE: The purpose of this study was to systematically assess asymptomatic changes (ACs), including subclinical hemorrhage, growth, or new lesion formation (NLF) during longitudinal follow-up of cerebral cavernous angiomas (CAs), and to correlate these with symptomatic hemorrhage (SH) during the same period and with clinical features of the disease. METHODS: One hundred ninety-two patients were included in this study, among 327 consecutive patients with CA, prospectively identified between September 2009 and February 2019. Included patients had undergone clinical and MRI follow-up, in conjunction with institutional review board-approved biomarker studies, and harbored ≥ 1 CA with a maximum diameter of ≥ 5 mm on T2-weighted MRI. Rates of AC and SH per lesion-year and patient-year were assessed using prospectively articulated criteria. In multifocal/familial cases, rates of NLF were also assessed. RESULTS: There were no differences in demographic or disease features among cases included or excluded in the study cohort, except for a higher proportion of included patients with CCM3 mutation. Follow-up was 411 patient-years (2503 lesion-years). The rate of AC was higher than the rate of SH (12.9% vs 7.5% per patient-year, and 2.1% vs 1.2% per lesion-year, both p = 0.02). Patients presenting with a prior history of SH had a higher rate of AC than those with other forms of presentation (19.7% and 8.2% per patient-year, respectively; p = 0.003). A higher rate of NLF on T2-weighted MRI (p = 0.03) was observed in patients with prior SH. Three of 6 solitary/sporadic and 2 of 28 multifocal/familial patients underwent resection of the lesion after AC. CONCLUSIONS: Rates of AC are greater than SH during prospective follow-up of CAs, and greater in cases with prior SH. AC may be a more sensitive biomarker of lesional activity, and a more efficient surrogate outcome in clinical trials than SH. Patients experiencing an AC are more likely to undergo a surgical intervention when CAs are solitary/sporadic than when they are multifocal/familial.

Clinical outcomes and prognostic factors for cavernous hemangiomas of the spinal cord: a retrospective cohort study

OBJECTIVE: Intramedullary cavernous hemangioma (CH) is a rare vascular lesion that is mainly characterized by the sudden onset of hemorrhage in young, asymptomatic patients, who then experience serious neurological deterioration. Despite the severity of this condition, the therapeutic approach and timing of intervention for CH remain matters of debate. The aim of this study was to evaluate the clinical characteristics of CH patients before and after surgery and to identify prognostic indicators that affect neurological function in these patients. METHODS: This single-center retrospective study included 66 patients who were treated for intramedullary CH. Among them, 57 underwent surgery and 9 patients received conservative treatment. The authors collected demographic, symptomology, imaging, neurological, and surgical data. Univariate and multivariate logistic regression analyses were performed to identify the prognostic indicators for neurological function. RESULTS: When comparing patients with stable and unstable gait prior to surgery, patients with unstable gait had a higher frequency of hemorrhagic episodes (52.4% vs 19.4%, p = 0.010), as assessed by the modified McCormick Scale. The lesion was significantly smaller in patients who underwent conservative treatment compared with surgery (2.5 ± 1.5 mm vs 5.9 ± 4.1 mm, respectively; p = 0.024). Overall, the patients experienced significant neurological recovery after surgery, but a worse preoperative neurological status was identified as an indicator affecting surgical outcomes by multivariate analysis (OR 10.77, 95% CI 2.88­40.36, p < 0.001). In addition, a larger lesion size was significantly associated with poor functional recovery in patients who had an unstable gait prior to surgery (8.6 ± 4.5 mm vs 3.5 ± 1.6 mm, p = 0.011). CONCLUSIONS: Once a hemorrhage occurs, surgical intervention should be considered to avoid recurrence of the bleeding and further neurological injury. In contrast, if the patients with larger lesion presented with worse preoperative functional status, surgical intervention could have a risk for aggravating the functional deficiencies by damaging the thinning cord parenchyma. Conservative treatment may be selected if the lesion is small, but regular neurological examination by MRI is needed for assessment of a change in lesion size and for detection of functional deterioration. ABBREVIATIONS: AIS = ASIA Impairment Scale; ASIA = American Spinal Injury Association; CH = cavernous hemangioma; EBL = estimated blood loss; JOA = Japanese Orthopaedic Association; mMS = modified McCormick Scale.

CCM3 and cerebral cavernous malformation disease.

Cerebral cavernous malformations (CCMs) are vascular lesions characterised by enlarged and irregular structure of small blood vessels in the brain, which can result in increased risk of stroke, focal neurological defects and seizures. Three different genes, CCM1/Krev/Rap1 Interacting Trapped 1, CCM2/MGC4607 and CCM3/PDCD10, are associated with the CCMs' progression, and mutations in one of three CCM genes cause CCM disease. These three CCM proteins have similar function in maintaining the normal structure of small blood vessels. However, CCM3 mutation results in a more severe form of the disease which may suggest that CCM3 has unique biological function in the vasculature. The current review focuses on the signalling pathways mediated by CCM3 in regulating endothelial cell junction, proliferation, migration and permeability. These findings may offer potential therapeutic strategies for the treatment of CCMs.

Radiosurgical, neurosurgical, or no intervention for cerebral cavernous malformations: A decision analysis.

INTRODUCTION: We aimed to evaluate the preferred treatment strategy for patients with symptomatic cerebral cavernous malformations (CCM). METHODS: In a decision model, we compared neurosurgical, radiosurgical, and conservative management. A literature review yielded the risks and outcomes of interventions, intracerebral hemorrhage (ICH), and seizures. Patients with CCM rated their quality of life to determine utilities. We estimated the expected number of quality-adjusted life years (QALYs) and the ICH recurrence risk over five years, according to mode of presentation and CCM location (brainstem vs. other). We performed analyses with a time horizon of five years. RESULTS: Using the best available data, the expected number of QALYs for brainstem CCM presenting with ICH or focal neurological deficit was 2.84 (95% confidence interval [CI]: 2.54-3.08) for conservative, 3.01 (95% CI: 2.86-3.16) for neurosurgical, and 3.03 (95% CI: 2.88-3.18) for radiosurgical intervention; those for non-brainstem CCM presenting with ICH or focal neurological deficit were 3.08 (95% CI: 2.85-3.31) for conservative, 3.21 (95% CI: 3.01-3.36) for neurosurgical, and 3.19 (95% CI: 2.98-3.37) for radiosurgical intervention. For CCM presenting with epilepsy, QALYs were 3.09 (95% CI: 3.03-3.16) for conservative, 3.33 (95% CI: 3.31-3.34) for neurosurgical, and 3.27 (95% CI: 3.24-3.30) for radiosurgical intervention. DISCUSSION AND CONCLUSION: For the initial five years after presentation, our study provides Class III evidence that for CCM presenting with ICH or focal neurological deficit conservative management is the first option, and for CCM presenting with epilepsy CCM intervention should be considered. More comparative studies with long-term follow-up are needed.

Precise CCM1 gene correction and inactivation in patient-derived endothelial cells: Modeling Knudson's two-hit hypothesis in vitro.

BACKGROUND: The CRISPR/Cas9 system has opened new perspectives to study the molecular basis of cerebral cavernous malformations (CCMs) in personalized disease models. However, precise genome editing in endothelial and other hard-to-transfect cells remains challenging. METHODS: In a proof-of-principle study, we first isolated blood outgrowth endothelial cells (BOECs) from a CCM1 mutation carrier with multiple CCMs. In a CRISPR/Cas9 gene correction approach, a high-fidelity Cas9 variant was then transfected into patient-derived BOECs using a ribonucleoprotein complex and a single-strand DNA oligonucleotide. In addition, patient-specific CCM1 knockout clones were expanded after CRISPR/Cas9 gene inactivation. RESULTS: Deep sequencing demonstrated correction of the mutant allele in nearly 33% of all cells whereas no CRISPR/Cas9-induced mutations in predicted off-target loci were identified. Corrected BOECs could be cultured in cell mixtures but demonstrated impaired clonal survival. In contrast, CCM1-deficient BOECs displayed increased resistance to stress-induced apoptotic cell death and could be clonally expanded to high passages. When cultured together, CCM1-deficient BOECs largely replaced corrected as well as heterozygous BOECs. CONCLUSION: We here demonstrate that a non-viral CRISPR/Cas9 approach can not only be used for gene knockout but also for precise gene correction in hard-to-transfect endothelial cells (ECs). Comparing patient-derived isogenic CCM1+/+ , CCM1+/- , and CCM1-/- ECs, we show that the inactivation of the second allele results in clonal evolution of ECs lacking CCM1 which likely reflects the initiation phase of CCM genesis.

Early onset cerebral amyloid angiopathy following childhood exposure to cadaveric dura.

Amyloid-ß transmission has been described in patients both with and without iatrogenic Creutzfeldt-Jakob disease; however, there is little information regarding the clinical impact of this acquired amyloid-ß pathology during life. Here, for the first time, we describe in detail the clinical and neuroimaging findings in 3 patients with early onset symptomatic amyloid-ß cerebral amyloid angiopathy following childhood exposure to cadaveric dura (by neurosurgical grafting in 2 patients and tumor embolization in a third). Our observations provide further in vivo evidence that cerebral amyloid angiopathy might be caused by transmission of amyloid-ß seeds (prions) present in cadaveric dura and have diagnostic relevance for younger patients presenting with suspected cerebral amyloid angiopathy. Ann Neurol 2019; 1-7 ANN NEUROL 2019;85:284-290.