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.

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.

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.

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.

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.

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.

Cavernous Malformation Hemorrhagic Presentation at Diagnosis Associated with Low 25-Hydroxy-Vitamin D Level.

BACKGROUND: Cavernous malformations (CM) are angiographically occult vascular malformations that may be incidental or present with intracerebral or spinal hemorrhage, seizures, or nonhemorrhagic focal neurologic deficit (FND). Recently in vitro data have suggested vitamin D may play a role in stabilizing CCM2 endothelial cells. Little is known about the effect of vitamin D in human CM disease. METHODS: Beginning in 2015, consecutive patients at our institution with radiologically confirmed CM were recruited to participate in a prospective clinical registry as well as 25-hydroxy-vitamin D study. A structured interview, survey, and examination were performed at baseline. Medical records and magnetic resonance imaging studies were reviewed and data collected included comorbid conditions, medication use, and location of CM. Standard definition of clinical hemorrhage, FND, and seizures was used. Univariate and multivariate logistic regression models were used, and OR, 95% CIs, and likelihood-ratio p values were calculated to determine the influence of the 25-hydroxy-vitamin D level on clinical presentation with hemorrhage. RESULTS: Of 213 patients enrolled in the clinical registry between January 2015 and October 2018, 70 participated in the vitamin D study (median age: 38.3 years; 51.4% female). Of the 70 participants, 30 (42.9%) presented with hemorrhage. 25-Hydroxy-vitamin D levels were performed within 1 year of symptoms in 64.1% of patients. Patients presenting with hemorrhage had a lower 25-hydroxy-vitamin D level compared to those presenting with seizure without hemorrhage, FND, or as an incidental finding (median 25.5 ng/mL; range 11-59 hemorrhage vs. median 31.0; range 14-60, no hemorrhage; p = 0.04). After adjusting for age, month of blood draw, and body mass index, 25-hydroxy-vitamin D remained a significant predictor of hemorrhagic presentation. Brainstem location also predicted hemorrhage at presentation. CONCLUSION: Low 25-hydroxy-vitamin D level was more common in patients with CM presenting with hemorrhage. This study supports the potential role of modifiable factor in the initial clinical presentation of CM. Further study is needed to determine the role of vitamin D on prospective hemorrhage risk and whether supplementation may be beneficial.

Brain capillary telangiectasias: from normal variants to disease.

BACKGROUND: Brain capillary telangiectasias (BCTs) are small, dilated capillary networks in the brain that are most commonly asymptomatic. Though rare, symptomatic cases of BCTs have been reported, and it is therefore important to understand the nature of these lesions in order to facilitate proper recognition. Relative to other intracranial vascular malformations, updated information on the various epidemiologic, radiographic, and pathologic features of BCTs within the published literature may be inadequate. METHODS: We searched the PubMed database for prior reports of symptomatically-manifested BCTs. Moreover, Google Scholar and PubMed were searched in order to review current epidemiologic, radiographic, pathologic, and pathogenetic features of BCTs. RESULTS: Forty-eight published studies were included for a total of 99 individual cases of BCTs with symptomatic manifestations. Thirty-three symptomatic BCTs were hemorrhagic in nature, while 66 were non-hemorrhagic. The mean age at presentation of hemorrhagic lesions was 25.5 years, and the most common location was the supratentorial CNS (54.5%) with motor disturbance representing the most commonly encountered presenting symptom (26.1%). 15.2% of hemorrhagic lesions were treated with surgical removal. In non-hemorrhagic lesions, the mean age at presentation was 39.8 years with the pons being the most common lesion location (78.5%) and headache being the most common presenting symptom (22.2%). 12.1% of patients with non-hemorrhagic lesions were treated with surgical removal. CONCLUSIONS: Despite their rarity, symptomatic BCTs, both hemorrhagic and non-hemorrhagic, can cause devastating neurological sequelae, potentially through multiple mechanisms. The large majority of these lesions do not require intervention, though surgical removal has been achieved with good outcome in select cases. Further documentation of symptomatic manifestations with or without surgical intervention is vital in order to further understand the clinical, surgical, and pathogenic implications of these less-appreciated vascular malformations.

Symptomatic developmental venous anomalies.

Cerebral developmental venous anomalies (DVAs) are variations of venous vascular anatomy related to an underdevelopment of either the superficial or deep venous emissary system, resulting in a dilated transmedullary vein fed by multiple smaller venous radicles responsible for drainage of normal brain parenchyma. While typically benign and found incidentally on imaging studies, DVAs can rarely be symptomatic. The radiographic appearance of DVAs, as well as their symptomatic manifestations, is diverse. Herein, we will discuss the pathophysiology of symptomatic DVAs while providing illustrative case examples depicting each of their pathogenic mechanisms.

The Influence of Physical Activity on Cavernous Malformation Hemorrhage.

BACKGROUND AND AIM: Cavernous malformations are low-flow vascular malformations of the central nervous system. Brainstem location and prior hemorrhage increase future hemorrhage risk. We sought to determine the influence of physical activity on hemorrhage risk. METHODS: Consecutive patients with radiologically confirmed cavernous malformations participated in a prospective registry with structured, baseline interviews, surveys, and examinations. Patients were asked about unusual events prior to initial clinical presentation. Medical records and MRIs were reviewed. Patients were surveyed about their physical activity after receiving their diagnosis. Annual follow-up surveys to patients ascertained new hemorrhages. Follow-up terminated at last follow-up, hemorrhage, surgery, or death. Univariate analysis assessed the risk of physical activities on prospective hemorrhage. RESULTS: Of 195 patients, 117 (60%) were female. Median diagnosis age was 41 years. After diagnosis, 103 (52.8%) patients returned the physical activity survey (cerebral n = 100; spine n = 3). Over 539.4 patient years, 23 had a prospective hemorrhage. Five patients were removed from analysis because they had less than 6 weeks of physical-activity exposure before censor. The remaining 98 had no difference in prospective hemorrhage risk than those patients participating greater than or equal to 3 times monthly in walking, running, greater than 20-pound or less than 20-pound weight lifting, or noncontact sports. Few (n = 5) reported contact-sport participation, scuba diving (n = 2), or high-altitude climbing (n = 1) greater than 3 times monthly. CONCLUSIONS: Aerobic activity and noncontact sports do not increase hemorrhage risk in cerebral cavernous malformation; patients should not be restricted. Less is known about contact sports, high-altitude climbing, scuba diving, and those with spinal-cord cavernous malformation.

Clinical presentation, natural history and outcomes of intramedullary spinal cord cavernous malformations.

OBJECTIVE: There is a paucity of literature investigating the clinical course of patients with spinal intramedullary cavernous malformations (ISCMs). We present a large case series of ISCMs to describe clinical presentation, natural history and outcomes of both surgical and conservative management. METHODS: We retrospectively reviewed the clinical course of patients diagnosed with ISCMs at our institution between 1995 and 2016. Haemorrhage was defined as clinical worsening in tandem with imaging changes visualised on follow-up MRI. Outcomes assessed included neurological status and annual haemorrhage rates. RESULTS: A total of 107 patients met inclusion criteria. Follow-up data were available for 85 patients. While 21 (24.7%) patients underwent immediate surgical resection, 64 (75.3%) were initially managed conservatively. Among this latter group, 16 (25.0%) suffered a haemorrhage during follow-up and 11 (17.2%) required surgical resection due to interval bleeding or neurological worsening. The overall annual risk of haemorrhage was 5.5% per person year. The rate among patients who were symptomatic and asymptomatic on presentation was 9.5% and 0.8%, respectively. Median time to haemorrhage was 2.3 years (0.1-12.3). Univariate analysis identified higher ISCM size (p=0.024), history of prior haemorrhage (p=0.013) and presence of symptoms (p=0.003) as risk factors for subsequent haemorrhage. Multivariable proportional hazards analysis revealed presence of symptoms to be independently associated with haemorrhage during follow-up (HR 9.39, CI 1.86 to 170.8, p=0.013). CONCLUSION: Large, symptomatic ISCMs appear to be at increased risk for subsequent haemorrhage. Surgery may be considered in such lesions to prevent rebleeding and subsequent neurological worsening.

Affected health domains in patients with brainstem cavernous malformations.

BACKGROUND: Brainstem cavernous malformations (CM) carry high risks of hemorrhage and neurologic morbidity. While much is published on physical effects of brainstem CM, very little is known about these patients' quality of life. This study aimed to assess the quality of life PROMIS-29 health domains of brainstem CM patients and identify quality of life predictors. METHODS: This was a cross-sectional study of adult patients with at least one brainstem CM identified by advertising on the Angioma Alliance website and from our institutional CM registry. A web-based questionnaire was administered and included self-reported information about the patient, cavernous malformation, residual clinical symptoms, and treatment. In addition, patients filled out the PROMIS-29 (version 1.0). The PROMIS-29 has 7 health domains and is standardized against the general population. We defined impaired quality of life as at least one out of 7 abnormal domains and used a 1 standard deviation cutoff for abnormal. We verified clinical and radiographic data to self-reported data in 28.8% of patients. RESULTS: A total of 104 patients (mean age of 46.5 ± 11.5 years; 77.9% females) were recruited. Most (82.7%) reported at least one symptomatic hemorrhagic event and 36.5% reported at least 1 surgical procedure. At least one abnormal PROMIS domain was present in 64.4% of patients with fatigue (34.6%), anxiety (35.6%), social (28.2%), and physical (27.9%) domains being the most common. Among patients with a Rankin Score of 0-2, 55% had at least one abnormal domain. Gait difficulty, but not age, sex, or surgery predicted impaired quality of life. CONCLUSION: More than half of patients with brainstem CM have impaired quality of life. Fatigue, anxiety, and social function, in addition to physical dysfunction, are common; practitioners should be aware of these concerns. PROMIS-29 provides additional information than modified Rankin Score and should be considered in clinical trials and when assessing treatment outcomes until a disease-specific outcome tool is available.

Infratentorial Developmental Venous Abnormalities and Inflammation Increase Odds of Sporadic Cavernous Malformation.

GOAL: Sporadic brain cavernous malformations commonly correlate with developmental venous anomalies; however, developmental venous anomalies may exist without cavernous malformations. Infratentorial location and specific angioarchitectural features of the developmental venous anomaly increase the odds of a concomitant malformation. Animal data also suggest chronic inflammatory disease, oxidative stress, and angiogenesis promote cavernous malformation development. We sought to determine potential clinical and radiologic factors promoting development of sporadic cavernous malformations. METHODS: One hundred and forty-five patients with sporadic, nonradiation-induced brain cavernous malformations (63 with radiologic-apparent and 82 with radiologic-occult developmental venous anomalies) were compared to developmental venous anomaly controls without associated malformation. Data collection included demographic information, comorbidities, medications at diagnosis, and location of the developmental venous anomaly and/or malformation. Logistic regression with likelihood ratios, odds ratios and 95% confidence intervals were calculated comparing malformation cases with controls. A similar analysis compared malformations with radiologic-apparent anomalies to controls. RESULTS: Compared to controls, cases were more likely to have had a major infectious illness (10.3% versus 2.3%; P = .0003 and/or chronic inflammatory disease (31.7% versus 21.3%; P = .0184) prior to diagnostic magnetic resonance imaging. Infratentorial location was more common in cavernous malformation cases (31.7% versus 15.7% controls; P ≤ .0001) with similar findings in cavernous malformation with radiologic-apparent developmental venous anomalies versus controls. CONCLUSIONS: Infratentorial developmental venous anomalies location, major infectious illness, and chronic inflammatory disorders increase the odds of sporadic cavernous malformation formation. Inflammation may promote local thrombosis of developmental venous anomalies, trigger angiogenic response through increased vascular permeability, or promote cavernous malformation through Toll-like receptor 4.

Natural History of Vertebrobasilar Dolichoectatic and Fusiform Aneurysms: A Systematic Review and Meta-Analysis.

BACKGROUND AND PURPOSE: Vertebrobasilar non-saccular and dolichoectatic aneurysms (VBDA) are a rare type of aneurysm and are generally associated with poor prognosis. In order to better characterize the natural history of VBDAs, we performed a systematic review and meta-analysis of the literature to determine rates of mortality, growth, rupture, ischemia, and intraparenchymal hemorrhage. MATERIALS AND METHODS: We searched the literature for longitudinal natural history studies of VBDA patients reporting clinical and imaging outcomes. Studied outcomes included annualized rates of growth, rupture, ischemic stroke, intracerebral hemorrhage (ICH), and mortality. We also studied the association between aneurysm morphology (dolichoectatic versus fusiform) and natural history. Meta-analysis was performed using a random-effects model using summary statistics from included studies. RESULTS: Fifteen studies with 827 patients and 5,093 patient-years were included. The overall annual mortality rate among patients with VBDAs was 13%/year (95% CI 8-19). Patients with fusiform aneurysms had a higher mortality rate than those with dolichoectatic aneurysms, but this did not reach statistical significance (12 vs. 8%, p = 0.11). The overall growth rate was 6%/year (95% CI 4-13). Patients with fusiform aneurysms had higher growth rates than those with dolichoectatic aneurysms (12 vs. 3%, p < 0.0001). The overall rupture rate was 3%/year (95% CI 1-5). Patients with fusiform aneurysms had higher rupture rates than those with dolichoectatic aneurysms (3 vs. 0%, p < 0.0001). The overall rate of ischemic stroke was 6%/year (95% CI 4-9). Patients with dolichoectatic aneurysms had higher ischemic stroke rates than those with fusiform aneurysms, but this did not reach statistical significance (8 vs. 4%, p = 0.13). The overall rate of ICH was 2%/year (95% CI 0-8) with no difference in rates between dolichoectatic and fusiform aneurysms (2 vs. 2%, p = 0.65). CONCLUSION: In general, the natural history of -VBDAs is poor. However, dolichoectatic and fusiform -VBDAs appear to have distinct natural histories with substantially higher growth and rupture associated with fusiform aneurysms. These findings suggest that these aneurysms should be considered separate entities. Further studies on the natural history of vertebrobasilar dolichoectatic and fusiform aneurysms with more complete follow-up are needed to better understand the risk factors for progression of these aneurysms.

Increased Prevalence of Cerebrovascular Disease in Hospitalized Patients with Marfan Syndrome.

BACKGROUND AND PURPOSE: Small studies have suggested that Marfan syndrome is associated with a number of cerebrovascular complications. We sought to determine whether a clinical diagnosis of Marfan syndrome is associated with a higher prevalence of cerebrovascular diseases than the general population by performing a case-control study of hospitalized patients in the Nationwide Inpatient Sample (NIS). METHODS: Using the 2000-2012 NIS, we performed a case-control study matching cases of Marfan syndrome to controls without such a diagnosis. The prevalence of various cerebrovascular diseases between the 2 groups were compared, and multivariate logistic regression was used to adjust for suspected comorbidities. RESULTS: Between 2000 and 2012, there were a total of 13,883 discharges carrying a diagnosis of Marfan syndrome. On univariate analysis, patients with Marfan syndrome were more likely to have a primary or secondary diagnosis of hemorrhagic stroke (0.5% versus 0.3%, odds ratio [OR] = 1.56, 95% confidence interval [CI] = 1.06-2.29, P = 0.02) as well as intracranial hemorrhage (subarachnoid hemorrhage [SAH] and hemorrhagic stroke) (0.3% versus 0.2%, OR = 1.72, 95% CI = 1.05-2.82, P = 0.03). Patients hospitalized with Marfan syndrome were significantly more likely to have carotid dissection (0.3% versus 0.0%, OR = 11.69, 95% CI = 3.60-38.08, P <. 0001) and cerebral aneurysms (0.2% versus 0.1%, OR = 3.67, 95% CI = 1.76-7.68, P = 0.0002). On multivariate analysis adjusted for age, race, and comorbidities, patients with Marfan syndrome had significantly higher odds of ischemic stroke (OR = 1.20, 95% CI = 1.02-1.43, P = 0.03), hemorrhagic stroke (OR = 1.75, 95% CI = 1.18-2.63, P = 0.005), carotid artery dissection (OR = 11.94, 95% CI = 4.23-50.03, P < 0.0001), and cerebral aneurysm (OR = 3.95, 95% CI = 1.95-8.90, P <0.0001). CONCLUSIONS: There is a modestly increased prevalence of ischemic stroke, hemorrhagic stroke, and cerebral aneurysms in hospitalized patients with Marfan syndrome when compared with controls.

Prevalence and Natural History of Superficial Siderosis: A Population-Based Study.

BACKGROUND AND PURPOSE: Superficial siderosis (SS) is characterized by hemosiderin deposition in the superficial layers of the central nervous system and can be seen during postmortem examination or with iron-sensitive magnetic resonance imaging techniques. The distribution of SS may predict the probable underlying cause. This study aimed to report the prevalence and natural history of SS in a population-based study. METHODS: Brain magnetic resonance imaging scans from the MCSA (Mayo Clinic Study of Aging), a population-based study of residents 50 to 89 years of age in Olmsted County, Minnesota, were reviewed. Participants with imaging consistent with SS were identified from 2011 through 2016. An inverse probability weighting approach was used to convert our observed frequencies to population prevalence of SS. Additional data abstracted included amyloid positron emission tomography, Apolipoprotein E genotype, coexisting cerebral microbleeds, and extent of SS. RESULTS: A total of 1412 participants had eligible magnetic resonance imaging scans. Two participants had infratentorial SS, restricted to the posterior fossa. Thirteen participants had cortical SS involving the cerebral convexities (7 focal and 6 disseminated). Only 3 of the participants with cortical SS (23%) also had cerebral microbleeds. The population prevalence of SS was 0.21% (95% confidence interval, 0-0.45) in those 50 to 69 years old and 1.43% (confidence interval, 0.53-2.34) in those over 69 years old. Apolipoprotein E ε2 allele was more common in those with SS (57.1% versus 15.0%; P<0.001). Compared with participants without SS, those with SS were also more likely to have a positive amyloid positron emission tomographic scan (76.9% versus 29.8%; P<0.001). CONCLUSIONS: SS may be encountered in the general elderly population. The association with increased amyloid burden and Apolipoprotein E ε2 genotype supports cerebral amyloid angiopathy as the most common mechanism. Longitudinal follow-up is needed to evaluate the risk of subsequent hemorrhage in cases of incidentally discovered SS.

Prevalence of cerebral cavernous malformations associated with developmental venous anomalies increases with age.

BACKGROUND AND PURPOSE: To test the hypothesis that the prevalence of cerebral cavernous malformation (CCM) associated with developmental venous anomalies (DVAs) increases with age, we studied the age-related prevalence of DVA-associated CCM among patients with DVAs. MATERIALS AND METHODS: Patients with DVAs on contrast-enhanced MRI exams performed over a 2-year period were included in this study. A single neuroradiologist reviewed all imaging exams for the presence of CCMs. Baseline demographic data collected included age, gender, presence of CNS neoplasm, history of cranial radiation, and history of seizure. Patients were divided into age groups based on decade of life. Cochran-Armitage trend tests were performed to determine if increasing age was associated with CCM prevalence. RESULTS: A total of 1689 patients with DVAs identified on contrast-enhanced MRI were included. Of these patients, 116 (6.9%) had a cavernous malformation associated with the DVA. There was a significant positive association between age and the prevalence of DVA-associated CCM (P = 0.002). The prevalence of DVA-associated CCM was 0.8% for the 0-10 age group, 1.6% for the 11-20 age group, 7.5% for the 21-30 age group, 9.5% for the 31-40 age group, 6.1% for the 41-50 age group, 6.3% for the 51-60 age group, 7.4% for the 61-70 age group, and 11.6% for the >70 age group (P < .0001). CONCLUSIONS: Our study demonstrated an age-related increase in prevalence of DVA-associated cavernous malformations among patients with DVAs. These findings suggest that DVA-associated cavernous malformations are acquired lesions.

Clinical Management of Cavernous Malformations.

PURPOSE OF REVIEW: This study aims to review the current epidemiology and clinical management of patients with cavernous malformations (CM). RECENT FINDINGS: Hemorrhage is the most feared complication and leads to morbidity in patients with CM. Multiple studies including three meta-analyses have provided useful estimates of hemorrhage risk, but have failed to identify a modifiable risk factor for prevention of cavernous malformation related hemorrhage. In treating the CM itself, surgical risk is weighed against the natural history. However, accumulating knowledge regarding the roles of CCM 1, 2, and 3 genes has led to the discovery of potential therapeutic targets. The risk of future hemorrhage in patients with CM is highest in those who have had previously clinical hemorrhages. Estimated risks are helpful in counseling patients and comparing to the risk of surgery. Future clinical trials of candidate medications are likely to target those patients with prior clinical hemorrhage in whom the surgical risk is deemed high.

A population-based study for 30-d hospital readmissions after acute ischemic stroke.

OBJECTIVE: To determine post-stroke 30-d readmission rate, its predictors, its impact on mortality and to identify potentially preventable causes of post-stroke 30-d readmission in a population-based study. PATIENTS AND METHODS: We identified all acute ischemic strokes (AIS) using the International Classification of Diseases 9th revision codes (433.x1, 434.xx and 436) via the Rochester Epidemiology Project (REP) between January 2007 and December 2011. Acute stroke care in Olmsted County is provided by two medical centers, Saint Marys Hospital and Olmsted Medical Center Hospital. All readmissions to these two hospitals were accounted for this study. Thirty-day readmission data was abstracted through manual chart review. The REP linkage database was used to identify the status (living/dead) of all patients at last follow up. RESULTS: Forty-one (7.6%, 95% CI 5.7%-10.2%) of total 537 AIS patients were readmitted 30-d post-stroke. In a multivariable logistic regression model, discharge to nursing home following index stroke (OR: 0.29, 95% CI 0.08-0.84) was an independent negative predictor of unplanned 30-d readmission. In a subgroup of patients with dementia, being married at time of index stroke was found to be a negative predictor of readmission (OR: 0.10, 95% CI 0.005-0.58). Only 2.8% of the patients had potentially preventable readmissions. Hospital readmission had no significant impact on patient's short-term (three months) or long-term (one or two years) mortality (p > 0.05). CONCLUSION: Post-stroke 30-d readmission rate is low in AIS patients from Olmsted County. Further research is needed in regarding discharge checklists, protocols and stroke transitional programs to reduce potentially preventable readmissions.