Quantitative image signature and machine learning-based prediction of outcomes in cerebral cavernous malformations.

PURPOSE: There is increasing interest in novel prognostic tools and predictive biomarkers to help identify, with more certainty, cerebral cavernous malformations (CCM) susceptible of bleeding if left untreated. We developed explainable quantitative-based machine learning models from magnetic resonance imaging (MRI) in a large CCM cohort to demonstrate the value of artificial intelligence and radiomics in complementing natural history studies for hemorrhage and functional outcome prediction. MATERIALS AND METHODS: One-hundred-eighty-one patients from a prospectively registered cohort of 366 adults with CCM were included. Fluid attenuated inversion recovery (FLAIR) T2-weighted brain images were preprocessed, and CCM and surrounding edema were segmented before radiomic feature computation. Minority class oversampling, dimensionality reduction and feature selection methods were applied. With prospective hemorrhage as primary outcome, machine learning models were built, cross-validated, and compared using clinico-radiologic, radiomic, and combined features. SHapley Additive exPlanations (SHAP) was used for interpretation to determine the radiomic features with most contribution to hemorrhage prediction. RESULTS: The highest performances in hemorrhage predictions on the test set were combining radiomic and clinico-radiological features with an area under the curve (AUC) of 83% using linear regression and selected features, and an F1 score of 61% and 85% sensitivity using K-nearest neighbors with principal component analysis (PCA). Multilayer perceptron had the best performance predicting modified Rankin Scale ≥ 2 with an AUC of 74% using PCA derived features. For interpretation of the selected radiomic signature XGBoost model, Shapley additive explanations highlighted 6 radiomic features contributing the most to hemorrhage prediction. CONCLUSION: Quantitative image-based modeling using machine learning has the potential to highlight novel imaging biomarkers that predict hemorrhagic and functional outcomes, ensuring more precise and personalized care for CCM patients.

Coronavirus Disease 2019 Infection in Cervical Artery Dissections.

OBJECTIVE: Most cervical artery dissection (CeAD) cases are spontaneous or due to minor traumas, and preceding viral infections have been suggested to be a triggering event for CeAD in some. Herein, we analyze the prevalence of coronavirus disease 2019 (COVID-19) in hospitalized patients with CeAD using a national database. METHODS: The National Inpatient Sample was queried from April 2020 to December 2020 for patients with a diagnosis of CeAD using International Classification of Diseases, 10th edition-Clinical Modification codes. Among these, patients with COVID-19 were identified. Multivariable logistic regression was conducted to assess the patient profile of those with COVID-19, in-patient mortality, and home discharge among patients with CeAD. RESULTS: There were 360 (2.32%) hospitalizations involving COVID-19 among 15,500 with CeAD. Concomitant acute ischemic stroke constituted 43.06% of those with a COVID-19 diagnosis, whereas it was 43.73% among those without a COVID-19 diagnosis ( P = 0.902). Home discharges were less common in patients with COVID-19 and CeAD compared to CeAD alone (34.85% vs. 48.63%; P = 0.03), but this was likely due to other factors as multivariate regression analysis did not show an association between COVID-19 and home discharges (odds ratio: 0.69; 95% CI: 0.39 to 1.25; P = 0.22). COVID-19 diagnosis had similar odds of inpatient mortality (odds ratio: 1.11; 95% CI: 0.43 to 2.84; P = 0.84). CONCLUSION: The prevalence of COVID-19 among hospitalized patients with CeAD is low with 2.32% of all CeAD cases. Concomitant COVID infection did not lead to an increased risk of stroke in CeAD. However, potentially worse functional outcomes (fewer home discharges) without an increase in mortality were seen in patients with COVID and CeAD.

Trial Readiness of Cavernous Malformations With Symptomatic Hemorrhage, Part I: Event Rates and Clinical Outcome.

BACKGROUND: Cerebral cavernous malformation with symptomatic hemorrhage (SH) are targets for novel therapies. A multisite trial-readiness project (https://www.clinicaltrials.gov; Unique identifier: NCT03652181) aimed to identify clinical, imaging, and functional changes in these patients. METHODS: We enrolled adult cerebral cavernous malformation patients from 5 high-volume centers with SH within the prior year and no planned surgery. In addition to clinical and imaging review, we assessed baseline, 1- and 2-year National Institutes of Health Stroke Scale, modified Rankin Scale, European Quality of Life 5D-3 L, and patient-reported outcome-measurement information system, Version 2.0. SH and asymptomatic change rates were adjudicated. Changes in functional scores were assessed as a marker for hemorrhage. RESULTS: One hundred twenty-three, 102, and 69 patients completed baseline, 1- and 2-year clinical assessments, respectively. There were 21 SH during 178.3 patient years of follow-up (11.8% per patient year). At baseline, 62.6% and 95.1% of patients had a modified Rankin Scale score of 1 and National Institutes of Health Stroke Scale score of 0 to 4, respectively, which improved to 75.4% (P=0.03) and 100% (P=0.06) at 2 years. At baseline, 74.8% had at least one abnormal patient-reported outcome-measurement information system, Version 2.0 domain compared with 61.2% at 2 years (P=0.004). The most common abnormal European Quality of Life 5D-3 L domains were pain (48.7%), anxiety (41.5%), and participation in usual activities (41.4%). Patients with prospective SH were more likely than those without SH to display functional decline in sleep, fatigue, and social function patient-reported outcome-measurement information system, Version 2.0 domains at 2 years. Other score changes did not differ significantly between groups at 2 years. The sensitivity of scores as an SH marker remained poor at the time interval assessed. CONCLUSIONS: We report SH rate, functional, and patient-reported outcomes in trial-eligible cerebral cavernous malformation with SH patients. Functional outcomes and patient-reported outcomes generally improved over 2 years. No score change was highly sensitive or specific for SH and could not be used as a primary end point in a trial.

Trial Readiness of Cavernous Malformations With Symptomatic Hemorrhage, Part II: Biomarkers and Trial Modeling.

BACKGROUND: Quantitative susceptibility mapping (QSM) and dynamic contrast-enhanced quantitative perfusion (DCEQP) magnetic resonance imaging sequences assessing iron deposition and vascular permeability were previously correlated with new hemorrhage in cerebral cavernous malformations. We assessed their prospective changes in a multisite trial-readiness project. METHODS: Patients with cavernous malformation and symptomatic hemorrhage (SH) in the prior year, without prior or planned lesion resection or irradiation were enrolled. Mean QSM and DCEQP of the SH lesion were acquired at baseline and at 1- and 2-year follow-ups. Sensitivity and specificity of biomarker changes were analyzed in relation to predefined criteria for recurrent SH or asymptomatic change. Sample size calculations for hypothesized therapeutic effects were conducted. RESULTS: We logged 143 QSM and 130 DCEQP paired annual assessments. Annual QSM change was greater in cases with SH than in cases without SH (P=0.019). Annual QSM increase by ≥6% occurred in 7 of 7 cases (100%) with recurrent SH and in 7 of 10 cases (70%) with asymptomatic change during the same epoch and 3.82× more frequently than clinical events. DCEQP change had lower sensitivity for SH and asymptomatic change than QSM change and greater variance. A trial with the smallest sample size would detect a 30% difference in QSM annual change during 2 years of follow-up in 34 or 42 subjects (1 and 2 tailed, respectively); power, 0.8, α=0.05. CONCLUSIONS: Assessment of QSM change is feasible and sensitive to recurrent bleeding in cavernous malformations. Evaluation of an intervention on QSM percent change may be used as a time-averaged difference between 2 arms using a repeated measures analysis. DCEQP change is associated with lesser sensitivity and higher variability than QSM. These results are the basis of an application for certification by the US Food and Drug Administration of QSM as a biomarker of drug effect on bleeding in cavernous malformations. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03652181.

Prevalence of Developmental Venous Anomalies in Association with Sporadic Cavernous Malformations on 7T MRI.

BACKGROUND AND PURPOSE: The etiology of sporadic cavernous malformations is not well-understood. However, recent evidence suggests that they may arise from a developmental venous anomaly. The goal of this study was to evaluate the prevalence of developmental venous anomalies associated with sporadic cavernous malformations using 7T MR imaging. MATERIALS AND METHODS: We retrospectively identified patients with a sporadic cavernous malformation imaged with 7T MR imaging between August 2019 and July 2022. Two raters determined whether a developmental venous anomaly was associated with each malformation. RESULTS: The study included 59 patients with a total of 61 cavernous malformations. Of the sixty-one, 44 (72%) had an associated developmental venous anomaly. An associated anomaly was most common for cavernous malformations in the brainstem (88%) compared with the cerebral hemispheres or cerebellum (60%-67%). CONCLUSIONS: By means of high-quality 7T imaging, most patients with a sporadic cavernous malformation were found to have an associated developmental venous anomaly. These findings support the hypothesis that cavernous malformations may arise secondary to hemodynamic abnormalities.

Are there differences in clinical presentation, radiologic findings, and outcomes in female patients with cavernous malformation?

BACKGROUND: Little data exist regarding sex differences in cavernous malformations (CM) patients. METHODS: From an ongoing, prospective registry of consenting adults with CM, we assessed the differences between male and female patients in regard to age at presentation, type of presentation, radiologic characteristics and prospective, symptomatic hemorrhage and or focal neurologic deficit (FND) risk and functional outcome. Cox proportional-hazard ratios and 95% confidence intervals with P values < 0.05 were considered significant in the outcome analysis. Familial form CM female patients were compared to sporadic form. RESULTS: As of 1/1/2023, our cohort comprised 386 people (58.0% female) after excluding radiation-induced CM. There were no demographic or clinical presentation differences between male and female patients. Radiological features did not differ between sexes, except that female, sporadic patients were more likely to have an associated developmental venous anomaly (DVA) (43.2% male vs. 56.2% female; p = 0.03). Overall, there was no difference in prospective symptomatic hemorrhage or functional outcome between sexes. Female sex was a predictor of symptomatic hemorrhage or FND in sporadic patients with ruptured CM (39.6% males versus 65.7% females; p = 0.02). The latter was not due to presence or absence of DVA. Familial CM females were more likely to have a spinal cord CM (15.2% familial female vs. 3.9% sporadic female; p = 0.001) and had a longer time to recurrent hemorrhage than sporadic female (2.2 years sporadic vs. 8.2 years familial; p = 0.0006). CONCLUSION: Minimal differences in clinical, radiologic, and outcomes were found in male versus female patients and familial versus sporadic females in the overall CM patient group. The finding that sporadic form female patients with history of prior hemorrhage had increased rates of prospective hemorrhage or FND compared to male patients raise the question whether to "lump" or "split" ruptured versus unruptured CM patients when analyzing risk factors for prospective hemorrhage in natural history studies.

Cavernous Angioma Symptomatic Hemorrhage (CASH) Trial Readiness II: Imaging Biomarkers and Trial Modeling.

Background: Quantitative susceptibility mapping (QSM) and dynamic contrast enhanced quantitative perfusion (DCEQP) MRI sequences assessing iron deposition and vascular permeability were previously correlated with new hemorrhage in cavernous angiomas. We assessed their prospective changes in cavernous angiomas with symptomatic hemorrhage (CASH) in a multisite trial readiness project ( clinicaltrials.gov NCT03652181 ). Methods: Patients with CASH in the prior year, without prior or planned lesion resection or irradiation were enrolled. Mean QSM and DCEQP of CASH lesion were acquired at baseline, and at 1- and 2-year follow-ups. Sensitivity and specificity of biomarker changes were analyzed in relation to predefined lesional symptomatic hemorrhage (SH) or asymptomatic change (AC). Sample size calculations for hypothesized therapeutic effects were conducted. Results: We logged 143 QSM and 130 DCEQP paired annual assessments. Annual QSM change was greater in cases with SH than in cases without SH (p= 0.019). Annual QSM increase by ≥ 6% occurred in 7 of 7 cases (100%) with recurrent SH and in 7 of 10 cases (70%) with AC during the same epoch, and 3.82 times more frequently than clinical events. DCEQP change had lower sensitivity for SH and AC than QSM change, and greater variance. A trial with smallest sample size would detect a 30% difference in QSM annual change in 34 or 42 subjects (one and two-tailed, respectively), power 0.8, alpha 0.05. Conclusions: Assessment of QSM change is feasible and sensitive to recurrent bleeding in CASH. Evaluation of an intervention on QSM percent change may be used as a time-averaged difference between 2 arms using a repeated measures analysis. DCEQP change is associated with lesser sensitivity and higher variability than QSM. These results are the basis of an application for certification by the U.S. F.D.A. of QSM as a biomarker of drug effect in CASH.

Clinical presentation, hemorrhage risk, and outcome in patients with familial cavernous malformations: a pragmatic prospective analysis of 75 patients.

OBJECTIVE: Newly diagnosed patients with a familial cavernous malformation (FCM) and their families are concerned about their future outlook, which is scarcely discussed in the literature. The authors studied a prospective contemporary cohort of patients with FCMs to assess demographics, mode of presentation, prospective risk of hemorrhage and seizures, need for surgery, and functional outcome over an extended interval. METHODS: A prospectively maintained database beginning January 1, 2015, of patients diagnosed with a cavernous malformation (CM) was queried. Data on demographics, radiological imaging, and symptoms at first diagnosis were collected in adult patients who gave their consent to prospective contact. Follow-up was done using questionnaires, in-person visits, and medical record review to assess for prospective symptomatic hemorrhage (i.e., the first hemorrhage after enrollment in the database), seizure, functional outcome measured by the modified Rankin Scale (mRS), and treatment. The prospective hemorrhage rate was calculated by the number of prospective hemorrhages divided by patient-years of follow-up censored at last follow-up, first prospective hemorrhage, or death. A Kaplan-Meier curve of survival free of hemorrhage was obtained comparing patients with versus without hemorrhage at the time of presentation and compared with a log-rank test for p < 0.05. RESULTS: A total of 75 patients with FCM were included, of whom 60% were female. The mean age at diagnosis was 41 ± 16 years. Most symptomatic or large lesions were located supratentorially. At first diagnosis, 27 patients had no symptoms, and the remaining were symptomatic. Over an average of 9.9 years, the rate of prospective hemorrhage was 4.0% per patient-year, and the rate of new seizure was 1.2% per patient-year, with 64% and 32% of patients experiencing at least one symptomatic hemorrhage and at least one seizure, respectively. Thirty-eight percent of the patients underwent at least 1 surgery and 5.3% underwent stereotactic radiosurgery. At the last follow-up, 83.0% of patients remained independent with an mRS score ≤ 2. CONCLUSIONS: The authors' findings provide clinically useful information on hemorrhage rate, seizure rate, the likelihood of surgery, and functional outcome. These findings can be helpful to practicing physicians when counseling patients with FCM and their families, who are often apprehensive about their future and well-being.

Clinical presentation, natural history, and outcomes for infantile intracranial cavernous malformations: case series and systematic review of the literature.

INTRODUCTION: Intracranial cavernous malformations (CMs) are rare vascular malformations of the central nervous system in children. Infantile patients, being a developmentally vulnerable age group, pose a special challenge for management of these lesions. We pooled data from infantile patients diagnosed at our institution and individual cases published in the literature to provide input towards therapeutic decision-making. METHODS: A systematic search of PubMed, MEDLINE, Embase, and Scopus was performed in accordance with PRISMA guidelines to identify all reported cases of intracranial CMs in the literature for infantile patients aged ≤ 2 years. In addition, cases from our institution diagnosed between 2010 and 2020 were also included. Individual cases were pooled and analyzed for clinical presentation, natural history, and outcomes from conservative and surgical management. RESULTS: A total of 36 cases were included, of which 32 were identified from the literature. Median age at presentation was 14 months (range: 2 days to 24 months) months; 53% (n = 19) were females. Most cavernomas (64%, 23/36) were supratentorial, while 30% (n = 11) were located in brainstem and 5.5% (n = 2) in the cerebellum. With the exception of one patient, all cases were reported to be symptomatic; seizures (n = 15/31, 48.3%) and motor deficits (n = 13/31, 42%) were the most common symptom modalities. A total of 13 patients were managed conservatively upon initial presentation. No symptomatic hemorrhages were observed during 26 total person-years of follow-up. A total of 77% (28/36) underwent surgery; either upfront (23/28, 82%) at initial presentation or following conservative management. Among 12 patients who had preoperative seizures, 11/12 (91.6%) achieved seizure freedom post-resection. Among 7 patients who presented with hemiparesis preoperatively, 5 (71%) demonstrated some improvement, while 1 remained unchanged, and another patient with a brainstem cavernous malformation had worsening of motor function postoperatively. Postoperative recurrence was noted in 3 cases (3/27, 11%). CONCLUSION: Annual risk of repeat hemorrhage may be low for infantile patients with intracranial cavernous malformations; however, better follow-up rates and higher number of cases are needed to make a definitive assertion. Surgical resection may be associated with high rates of epilepsy cure and provide improvement in neurological function in a select number of cases.

Female Hormone Therapy and Risk of Intracranial Hemorrhage From Cerebral Cavernous Malformations: A Multicenter Observational Cohort Study.

BACKGROUND AND OBJECTIVES: Female hormone therapy (oral contraception in female patients of reproductive age and menopausal hormone therapy in postmenopausal patients) is not withheld from patients with cerebral cavernous malformations (CCMs), although the effects of these drugs on the risk of intracranial hemorrhage are unknown. We investigated the association between female hormone therapy and intracranial hemorrhage in female patients with CCM in 2 large prospective, multicenter, observational cohort studies. METHODS: We included consecutive patients with a CCM. We compared the association between use of female hormone therapy and the occurrence of intracranial hemorrhage due to the CCM during up to 5 years of prospective follow-up in multivariable Cox proportional hazards regression. We performed an additional systematic review through Ovid MEDLINE and Embase from inception to November 2, 2021, to identify comparative studies and assess their intracranial hemorrhage incidence rate ratio according to female hormone therapy use. RESULTS: Of 722 female patients, aged 10 years or older at time of CCM diagnosis, 137 used female hormone therapy at any point during follow-up. Female hormone therapy use (adjusted for age, mode of presentation, and CCM location) was associated with an increased risk of subsequent intracranial hemorrhage (46/137 [33.6%] vs 91/585 [15.6%] and adjusted hazard ratio 1.56, 95% CI 1.09-2.24; p = 0.015). Use of oral contraceptives in female patients aged 10-44 years adjusted for the same factors was associated with a higher risk of subsequent intracranial hemorrhage (adjusted hazard ratio 2.00, 95% CI 1.26-3.17; p = 0.003). Our systematic literature search showed no studies reporting on the effect of female hormone therapy on the risk of intracranial hemorrhage during follow-up. DISCUSSION: Female hormone therapy use is associated with a higher risk of intracranial hemorrhage from CCMs. These findings raise questions about the safety of female hormone therapy in clinical practice in patients with CCM. Further studies evaluating clinical factors raising risk of thrombosis may be useful to determine which patients may be most susceptible to intracranial hemorrhage. CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that female hormone therapy use is associated with a higher risk of intracranial hemorrhage in patients with CCM.

Use of intravascular optical coherence tomography to confirm the diagnosis of a carotid web in a patient with recurrent ipsilateral embolic strokes and evaluate the response to stenting.

A Carotid web (CaW) is defined as a focal shelf-like projection of non-atheromatous, fibrous tissue along the posterior wall of the carotid bulb. CaW are rare and commonly overlooked lesions increasingly recognized as a cause of stroke in otherwise healthy patients. Intravascular imaging modalities such as intravascular ultrasound and optical coherence tomography (OCT) have been proposed as an adjunct to digital subtraction angiography for the evaluation of CaW. However, the use of OCT in CaW has yet to be described. This report investigated the utility of OCT as an adjunct imaging modality in the evaluation of CaW morphology in a young patient with recurrent ischemic strokes.

The Influence of Select Medications on Prospective Hemorrhage Risk in Patients with Spinal or Cerebral Cavernous Malformations.

BACKGROUND: Effects of select medications on hemorrhage risk in patients with cerebral or spinal cavernous malformations (CMs) are unknown. METHODS: From a single-institution prospective cohort of patients with CM (2015-2021), demographics, mode of clinical presentation, and radiographic data were collected. Follow-up was performed with electronic medical record review, in-person visits, and written surveys. Select medication use was ascertained from the time of CM diagnosis to a censor date of first prospective symptomatic hemorrhage, complete surgical excision of sporadic form CM, last follow-up, or death. Using Cox proportional hazards regression model, we assessed effects of antithrombotic agents, fish oil, selective serotonin reuptake inhibitors (SSRIs), vitamin E and D supplementation, statins, and beta blockers on prospective hemorrhage risk. RESULTS: The study included 364 patients with spinal or cerebral CM (58.0% female; 20.0% familial form; 42.3% presentation to medical attention owing to hemorrhage; 25.8% brainstem location). During a follow-up of 2018 patient-years, 103 prospective hemorrhages occurred. No studied medications increased the prospective CM hemorrhage risk. Antithrombotics, vitamin D supplementation, fish oil, and SSRI were associated with lower hemorrhage risk even after adjusting for age at diagnosis, hemorrhage at diagnosis, and brainstem location. CONCLUSIONS: Use of select medications with antithrombotic properties do not increase the risk of CM hemorrhage. Vitamin D supplementation, any antithrombotic agent, fish oil, and SSRI were associated with a lower prospective hemorrhage risk. Further studies should evaluate the mechanism of action and potential benefit of these select medications.

Baseline Characteristics of Patients With Cavernous Angiomas With Symptomatic Hemorrhage in Multisite Trial Readiness Project.

BACKGROUND AND PURPOSE: Brain cavernous angiomas with symptomatic hemorrhage (CASH) have a high risk of neurological disability from recurrent bleeding. Systematic assessment of baseline features and multisite validation of novel magnetic resonance imaging biomarkers are needed to optimize clinical trial design aimed at novel pharmacotherapies in CASH. METHODS: This prospective, multicenter, observational cohort study included adults with unresected, adjudicated brain CASH within the prior year. Six US sites screened and enrolled patients starting August 2018. Baseline demographics, clinical and imaging features, functional status (modified Rankin Scale and National Institutes of Health Stroke Scale), and patient quality of life outcomes (Patient-Reported Outcomes Measurement Information System-29 and EuroQol-5D) were summarized using descriptive statistics. Patient-Reported Outcomes Measurement Information System-29 scores were standardized against a reference population (mean 50, SD 10), and one-sample t test was performed for each domain. A subgroup underwent harmonized magnetic resonance imaging assessment of lesional iron content with quantitative susceptibility mapping and vascular permeability with dynamic contrast-enhanced quantitative perfusion. RESULTS: As of May 2020, 849 patients were screened and 110 CASH cases enrolled (13% prevalence of trial eligible cases). The average age at consent was 46±16 years, 53% were female, 41% were familial, and 43% were brainstem lesions. At enrollment, ≥90% of the cohort had independent functional outcome (modified Rankin Scale score ≤2 and National Institutes of Health Stroke Scale score <5). However, perceived health problems affecting quality of life were reported in >30% of patients (EuroQol-5D). Patients had significantly worse Patient-Reported Outcomes Measurement Information System-29 scores for anxiety (P=0.007), but better depression (P=0.002) and social satisfaction scores (P=0.012) compared with the general reference population. Mean baseline quantitative susceptibility mapping and permeability of CASH lesion were 0.45±0.17 ppm and 0.39±0.31 mL/100 g per minute, respectively, which were similar to historical CASH cases and consistent across sites. CONCLUSIONS: These baseline features will aid investigators in patient stratification and determining the most appropriate outcome measures for clinical trials of emerging pharmacotherapies in CASH.

Relationship of brainstem infarction to rupture of nonsaccular vertebrobasilar aneurysms.

OBJECTIVE: Symptomatic nonsaccular vertebrobasilar aneurysms (NSVBAs) are associated with high rates of aneurysm-related death. Anecdotal evidence suggests that brainstem infarction may be a harbinger of aneurysm rupture. The authors aimed to investigate the association between brainstem infarction and subsequent NSVBA rupture. METHODS: The clinical records and radiographic imaging studies of patients presenting to the authors' institution between 1996 and 2019 for evaluation and management of an NSVBA were retrospectively reviewed to determine the effect of perforating artery infarction on the natural history of NSVBAs. Kaplan-Meier curves for patients with and patients without perforator infarction were constructed, and predictors of aneurysm rupture were identified using a multivariate Cox proportional hazards model. RESULTS: There were 98 patients with 591.3 person-years of follow-up who met the inclusion criteria for analysis. There were 20 patients who experienced perforator infarction during follow-up. Ten patients (10.2%) experienced aneurysm rupture during follow-up and 26 patients (26.5%) died due to aneurysm-related complications, with annual rates of rupture and aneurysm-related death of 1.7% and 4.4%, respectively. Five patients with a perforator infarction later experienced aneurysm rupture, with a median time between infarction and rupture of 3 months (range 0-35 months). On multivariate analysis, the presence of intraaneurysmal thrombus (risk ratio [RR] 4.01, 95% confidence interval [CI] 1.12-14.44, p = 0.033) and perforator infarction (RR 6.37, 95% CI 1.07-37.95, p = 0.042) were independently associated with risk of aneurysm rupture. CONCLUSIONS: NSVBAs continue to be extremely challenging clinical entities with a poor prognosis. These results suggest that brainstem infarction due to perforating artery occlusion may be a harbinger of near-term aneurysm rupture.

A Roadmap for Developing Plasma Diagnostic and Prognostic Biomarkers of Cerebral Cavernous Angioma With Symptomatic Hemorrhage (CASH).

BACKGROUND: Cerebral cavernous angioma (CA) is a capillary microangiopathy predisposing more than a million Americans to premature risk of brain hemorrhage. CA with recent symptomatic hemorrhage (SH), most likely to re-bleed with serious clinical sequelae, is the primary focus of therapeutic development. Signaling aberrations in CA include proliferative dysangiogenesis, blood-brain barrier hyperpermeability, inflammatory/immune processes, and anticoagulant vascular domain. Plasma levels of molecules reflecting these mechanisms and measures of vascular permeability and iron deposition on magnetic resonance imaging are biomarkers that have been correlated with CA hemorrhage. OBJECTIVE: To optimize these biomarkers to accurately diagnose cavernous angioma with symptomatic hemorrhage (CASH), prognosticate the risk of future SH, and monitor cases after a bleed and in response to therapy. METHODS: Additional candidate biomarkers, emerging from ongoing mechanistic and differential transcriptome studies, would further enhance the sensitivity and specificity of diagnosis and prediction of CASH. Integrative combinations of levels of plasma proteins and characteristic micro-ribonucleic acids may further strengthen biomarker associations. We will deploy advanced statistical and machine learning approaches for the integration of novel candidate biomarkers, rejecting noncorrelated candidates, and determining the best clustering and weighing of combined biomarker contributions. EXPECTED OUTCOMES: With the expertise of leading CA researchers, this project anticipates the development of future blood tests for the diagnosis and prediction of CASH to clinically advance towards precision medicine. DISCUSSION: The project tests a novel integrational approach of biomarker development in a mechanistically defined cerebrovascular disease with a relevant context of use, with an approach applicable to other neurological diseases with similar pathobiologic features.

Influence of Pregnancy on Hemorrhage Risk in Women With Cerebral and Spinal Cavernous Malformations.

BACKGROUND AND PURPOSE: Pregnancy as a hemorrhage risk factor in women with cavernous malformations (CMs) is controversial. We describe prospective hemorrhage risk in women who become pregnant after an established CM diagnosis. METHODS: Beginning in 2015, we recruited consecutive patients with radiologically confirmed CM of the brain or spinal cord to participate in a prospective registry. Participants underwent a baseline and annual medical record review, imaging review, and annual surveys to ascertain pregnancies, deliveries, and neurological complications. We collected prospective hemorrhage data on reproductive age women. We calculated prospective hemorrhage rates on childbearing age patients based on the number of hemorrhages occurring post-CM diagnosis during pregnancy and nonpregnancy, divided by the years of follow-up and censored at last follow-up, age 46, or surgery in sporadic-form CM. The hemorrhage rates were compared and the 95% CI presented with a P value of <0.05. RESULTS: Of 160 women, 90 presented with CM under the age of 46 (average age 31.6 years; 25.6% familial form; 46.7% with hemorrhage; 24.4% brain stem location). These 90 patients had 136 pregnancies before CM diagnosis; 36 pregnancies occurred at or after the diagnosis of CM. Four patients had a hemorrhage while pregnant or postpartum leading to the first CM diagnosis. During 402.6 years of follow-up while not pregnant, 42 hemorrhages occurred prospectively yielding a 10.4% per year (95% CI, 7.5-14.0) risk of hemorrhage while not pregnant. No hemorrhages occurred during 32 prospective pregnancies (26 live births including 1 twinset and 7 nonviable fetuses) after CM diagnosis during 26.9 years of pregnancy time yielding a rate of 0% per year (95% CI, 0-13.6). We found no statistical difference in the rates of hemorrhage during pregnant and nonpregnant time (P=0.09). No hemorrhage occurred during delivery. CONCLUSIONS: Our prospective data suggest that pregnancy does not increase the risk of hemorrhage in women with a known brain or spinal cord CM and that vaginal delivery is safe in appropriate candidates.

De novo hemorrhagic sporadic cavernous malformation appearance after COVID-19 respiratory infection: illustrative case.

BACKGROUND: Little is known about whether coronavirus disease 2019 (COVID-19) influences cavernous malformation (CM) formation or hemorrhage risk. OBSERVATIONS: The authors present the case of a 31-year-old patient who developed a hemorrhagic, de novo CM in the setting of a developmental venous anomaly within 3 months of COVID-19 respiratory disease. The authors speculate that COVID-19 disease stimulated formation of the CM through TLR4 inflammatory pathways and subsequently led to the hemorrhagic presentation because of hypercoagulability related to the disease. LESSONS: This case raises the possibility that COVID-19 may be a risk factor for de novo development of CMs in predisposed patients.

Giant Fusiform and Dolichoectatic Aneurysms of the Basilar Trunk and Vertebrobasilar Junction-Clinicopathological and Surgical Outcome.

BACKGROUND: Giant fusiform and dolichoectatic aneurysms of the basilar trunk and vertebrobasilar junction (BTVBJ-GFDA) are extremely difficult to treat. OBJECTIVE: To evaluate factors influencing survival and outcome of BTVBJ-GFDA by performing a retrospective multicenter cohort study. METHODS: A total of 32 patients with BTVBJ-GFDA were included in this study. Clinicopathological characteristics, treatment measures, and outcomes were collected from medical records and imaging studies. Autopsy and histological findings of the aneurysm and adjacent brain tissue were also obtained in 9 cases. RESULTS: A total of 11 patients did not undergo surgery, of whom 10 died; 3 from progressive brainstem compression, 4 from subarachnoid hemorrhage, 2 from brainstem infarction, and 1 from associated atherosclerotic disease. The remaining 21 patients underwent a surgical treatment, consisting of immediately proximal parent artery occlusion, remotely proximal parent artery occlusion, clip reconstruction, and distal bypass and achieved significantly longer overall survival compared with those who received conservative therapy (adjusted hazard ratio 1.508, 95% CI 1.058-2.148, P = .02). Histological examination of the aneurysms demonstrated staged clots, open lumen, and intrathrombotic channels with endothelial lining. The patients younger than 45 yr of age showed statistically longer survival than those equal and older than 45 yr (P = .03). CONCLUSION: Surgical intervention achieved greater survival than conservative management in BTVBJ-GFDA. Narrow ideal treatment window of the blood flow within the aneurysm to maintain sufficient but not excess supply should be targeted based on the hemodynamics of both the posterior communicating arteries and perforating vessel collaterals.