Stadnik, Agnieszka

Background A recent randomized prospective controlled trial demonstrated that atorvastatin for up to 2 years was safe but did not significantly alter rebleeding in cerebral cavernous malformations. However, any consequences of discontinuing atorvastatin remain unknown. We hypothesized that symptomatic hemorrhage (SH) recurs more frequently in cerebral cavernous malformations after discontinuation of atorvastatin than placebo. Methods We conducted a 12‐month posttreatment follow‐up of patients enrolled in the Atorvastatin Therapy in Cavernous Angiomas with Symptomatic Hemorrhage Exploratory Proof of Concept (AT CASH EPOC) trial (41 randomized to atorvastatin, 39 to placebo) to identify potential recurrent SH after trial drug discontinuation. Every SH was adjudicated by review of imaging and corresponding symptoms. Patients were excluded from follow‐up for <90% compliance with study drug, for its discontinuation <3 months after trial enrollment, for statin reinitiation <3 months after discontinuation, or for lack of follow‐up. Cases were censored during follow‐up upon cerebral cavernous malformation resection/radiation or later statin reinitiation. Results Follow‐up included 33 patients who had been randomized to placebo and 32 who had taken atorvastatin. Four SH events occurred at 3, 49, 84, and 225 days after atorvastatin discontinuation, and 1 SH at 395 days after discontinuing placebo. There was significantly lower symptomatic hemorrhage‐free survival in the atorvastatin‐discontinuation group (log‐rank χ 2 =4.136, P =0.042). The hazard ratio was 0.162 (95% CI, 0.027–0.977) for placebo versus atorvastatin discontinuation. Conclusions Discontinuation of atorvastatin was associated with a higher risk of recurrent SH compared with placebo discontinuation. Additional studies are warranted to confirm this hypothesis‐generating observation, examine potential mechanisms, and how best to mitigate this risk. REGISTRATION URL: https://www.clinicaltrials.gov ; Unique identifier: NCT02603328.

Background: There is much interest in drug development to prevent rebleeding after symptomatic hemorrhage (SH) in cerebral cavernous malformations (CCM) and its neurologic sequelae. A recent randomized prospective controlled trial (AT CASH EPOC clinicaltrials.gov NCT02603328) demonstrated that atorvastatin for up to 2 years was safe but did not significantly alter CCM iron deposition or SH rates. However, the consequences of discontinuing atorvastatin in CCM patients remain unknown. Given reports of rebound effects with discontinuation of statins, we here hypothesize that SH recurs more frequently in hemorrhagic CCMs after discontinuation of atorvastatin than placebo. Methods: We conducted 12-month (±1 month) post-treatment follow-up of all 80 patients randomized in the AT CASH EPOC trial (41 atorvastatin, 39 placebo) to identify potential recurrent SH from the date of trial drug discontinuation. Every SH was adjudicated by review of imaging and corresponding symptoms. Patients were excluded for < 90% compliance with study drug or its discontinuation <3 months during the trial, and for lack of follow-up. Cases were censored during follow-up upon CCM resection/radiation or atorvastatin initiation/re-initiation. Results: Follow-up included 33 patients who had been randomized to placebo and 32 who had taken atorvastatin.During follow-up, 4 SH events occurred at 3, 49, 84, and 225 days after atorvastatin discontinuation, and only 1 SH 395 days after discontinuing placebo. Kaplan–Meier curves demonstrated significantly lower symptomatic hemorrhage-free survival in the atorvastatin-discontinuation group (log-rank chi=4.136, p=0.042). The Gehan–Breslow–Wilcoxon test (chi=4.080, p=0.043) highlighted early divergence in recurrent SH risk. The hazard ratio was 0.162 (95% CI 0.027–0.977) for placebo vs. atorvastatin discontinuation. Conclusion: While there was no difference in SH rates during 2 years of treatment with atorvastatin versus placebo in randomized clinical trial, discontinuation of atorvastatin was associated with a significantly higher and earlier risk of recurrent SH compared with placebo discontinuation. This raises concern for a rebound effect during the year after statin withdrawal in hemorrhagic CCM patients, potentially mediated by reactivation of Rho-associated kinase. Additional studies are warranted to confirm these observations and to assess whether statin tapering or maintenance therapy can mitigate the risk of discontinuation in hemorrhagic CCM.

Introduction: Functional outcome scales are commonly used in neurological clinical trials. Prior studies suggested that these scales may reflect symptomatic hemorrhage (SH), but their performance in detecting treatment effects has not been assessed in clinical trials of cerebral cavernous malformations (CCM). And they have not been correlated with CCM bleeding as reflected by lesional iron content assessed by quantitative susceptibility mapping (QSM) MRI. Hypothesis: We hypothesized that functional outcome measures would detect differences between treatment arms in a randomized clinical trial of hemorrhagic CCM, and reflect new SH or a ≥6% increase in mean lesional QSM reflective of CCM bleeding. Methods: Eighty adults with CCM-related SH in the prior 12 months of enrollment were randomized 1:1 to atorvastatin 80 mg/day or placebo for 2 years. Functional outcomes, including mRS, EQ-5D index, EQ-VAS, and PROMIS-29 domains, were collected at baseline, Year 1, and Year 2. Analyses were conducted in 63 participants (32 atorvastatin, 31 placebo) in the modified intention-to-treat trial cohort who had contributed at least one paired annual clinical and imaging assessment. Results: No significant differences were found between atorvastatin and placebo groups in any functional outcome measure across timepoints. Rates of functional decline and improvement were comparable, except for PROMIS Fatigue which improved more in the atorvastatin than placebo patients from baseline to Year 1 (p=0.019). Pooled analyses showed that several functional domains had strong specificity for identifying SH. PROMIS Sleep Disturbance decline from baseline to Year 2 was associated with SH (p=0.0045; specificity 92.3%, sensitivity 57.1%). A ≥10-point drop in EQ-VAS from baseline to Year 1 identified all SH cases during that interval (p=0.007; sensitivity 100%, specificity 83.6%). Functional decline had low sensitivity in detecting CCM bleeding on QSM, though specificity was high (>75%) across domains. Conclusions: Atorvastatin did not influence functional change over 2 years by any measure. PROMIS Sleep Disturbance and EQ-VAS demonstrated high specificity, and in the case of EQ-VAS also a high sensitivity for identifying SH. Functional outcomes across domains also had high specificity for occult bleeding in CCMs as measured by QSM. Poor sensitivity and consistent improvements over time demonstrate the limitations of functional outcome measures as endpoints of drug effects on CCM bleeding.

Background: It is not clear if changes in lesion volume might represent a clinically relevant and statistically advantageous outcome parameter in early phase trials of novel drugs aimed at preventing bleeding in cerebral cavernous malformations (CCM). Methods: We analyzed the modified intention to treat cohort (33 patients receiving atorvastatin and 31 placebo) who contributed at least one paired imaging biomarker in the recently completed double-blinded randomized controlled AT CASH EPOC trial (clinicaltrials.gov NCT02603328). We examined prospective changes in CCM lesion volume and correlated these with symptomatic hemorrhage (SH) events. We contemporaneously assessed changes in lesional iron content by quantitative susceptibility mapping (QSM) on MRI, and objective (mRS) and subjective (EQ-VAS) functional status. We also simulated sample sizes needed to detect potential effects of a drug on lesion volume. Results: There was excellent correlation between independently assessed maximum lesion diameter and CCM lesion volume (R 2 = 0.68, P<0.0001). The mean (SD) percentage change in lesion volume per year was +6 (65) and +18 (94) in atorvastatin and placebo patients, respectively (P= 0.43). All cases with SH had increases in lesion volume as well as increases in mean lesional iron content by QSM, and most had declines in functional status on mRS and EQ-VAS. But there were many cases with increases in lesion volume with improved functional status or decreased mean lesional QSM, and other cases with worsening in function or increased lesional QSM and decreased lesion volume. There were no significant correlations of changes in lesion volume with concomitant changes in mean lesional QSM, mRS or EQ-VAS (all R/R 2 <0.5 and Bonferroni corrected P>0.05), including in brainstem lesions analyzed separately. Sample size simulations indicate larger numbers of cases needed to demonstrate a drug effect on changes in lesion volume than those needed to detect an effect on QSM change with a=0.05 and b=0.8, and even larger samples to detect effects on the proportion of cases with increased or decreased lesion volume. Conclusion: Changes in lesion volume occur frequently in CCM lesions after recent SH, but do not correlate with measures of bleeding in the lesions, nor appear to reflect functional changes. And they are not statistically advantageous in comparison to QSM measures for detecting potential drug effects.

BACKGROUND AND OBJECTIVES: It is not clear whether changes in lesion volume might represent a clinically relevant and statistically advantageous outcome parameter in early phase trials aimed at preventing bleeding in cerebral cavernous malformations (CCM). METHODS: We examined prospective changes in CCM lesion volume in the double-blinded AT CASH EPOC trial (clinicaltrials.gov NCT02603328). We correlated these with symptomatic hemorrhage (SH) events, contemporaneously assessed changes in lesional iron content by quantitative susceptibility mapping (QSM) on MRI, and objective (modified Rankin Scale (mRS)) and subjective (Euro-QoL Visual Analog Scale [EQ-VAS]) functional status. We also simulated sample sizes needed to detect potential effects on lesion volume. RESULTS: There was excellent correlation between independently assessed maximum lesion diameter and CCM lesion volume (R 2 = 0.68, P < .0001). The mean (SD) percentage change in lesion volume per year was +6 (65) and +18 (94) in atorvastatin and placebo patients, respectively ( P = .43). All cases with SH had increases in lesion volume and increases in mean lesional iron content by QSM, and most had declines in functional status on mRS and EQ-VAS, but there were no overall meaningful correlations of changes in lesion volume with concomitant changes in mean lesional QSM, mRS, or EQ-VAS (all R/R 2 < 0.5 and Bonferroni corrected P > .05), including in brainstem lesions analyzed separately. Sample size simulations indicate larger case numbers needed to demonstrate an effect on change in lesion volume than those needed to detect an effect on QSM change with α = 0.05 and β = 0.8, and even larger samples to detect effects on the number of cases with increased or decreased lesion volume. CONCLUSION: Changes in lesion volume occur frequently in CCM lesions after recent SH, but do not correlate with biomarkers of lesional bleeding, nor reflect functional changes, and are not statistically advantageous compared with QSM measures in detecting potential drug effects.

Features of new bleeding on conventional imaging in cerebral cavernous malformations (CCMs) often disappear after several weeks, yet the risk of rebleeding persists long thereafter. Increases in mean lesional quantitative susceptibility mapping (QSM) ≥ 6% on MRI during 1 year of prospective surveillance have been associated with new symptomatic hemorrhage (SH) during that period. The authors hypothesized that QSM at a single time point reflects features of hemorrhage in the prior year or potential bleeding in the subsequent year. Twenty-eight features were extracted from 265 QSM acquisitions in 120 patients enrolled in a prospective trial readiness project, and machine learning methods examined associations with SH and biomarker bleed (QSM increase ≥ 6%) in prior and subsequent years. QSM features including sum variance, variance, and correlation had lower average values in lesions with SH in the prior year (p < 0.05, false discovery rate corrected). A support-vector machine classifier recurrently selected sum average, mean lesional QSM, sphericity, and margin sharpness features to distinguish biomarker bleeds in the prior year (area under the curve = 0.61, 95% CI 0.52–0.70; p = 0.02). No QSM features were associated with a subsequent bleed. These results provide proof of concept that machine learning may derive features of QSM reflecting prior hemorrhagic activity, meriting further investigation. Clinical trial registration no.: NCT03652181 ( ClinicalTrials.gov )

OBJECTIVE The American Association of Neurological Surgeons (AANS) and Congress of Neurological Surgeons (CNS) Section on Pediatric Neurological Surgery domestic traveling fellowship was created to cover the travel and living expenses for a North American neurosurgery resident for 1 month at another institution to gain experience in pediatric neurosurgery. The objective of this work was to guide future direction by surveying past recipients about the fellowship and its impact on their training and career. METHODS Historical data have been maintained by the AANS/CNS Executive Committee and past and current chairs of the Traveling Fellowship Subcommittee. A 10-question REDCap survey was emailed to all previous fellowship recipients. RESULTS There have been 58 recipients of the traveling fellowship since 1998. The most common host program was Boston Children’s Hospital (n = 21), followed by The Hospital for Sick Children (n = 12). Excluding recent recipients after 2017 who may still be working toward certification, 20 of 38 (53%) recipients have been certified by the American Board of Pediatric Neurological Surgery (ABPNS). Twenty-four of 49 (49%) recipients completed the survey. Twenty (83.3%) respondents were either ABPNS certified or planning to seek certification, 17 (70.8%) respondents’ practices consisted of > 50% patients aged ≤ 21 years, and 18 (75%) spent 4–8 weeks at the host program, which was longer than the 1 month funded by the stipend. Twenty-two (91.7%) respondents would recommend the traveling fellowship to a resident interested in pediatric neurosurgery, and 18 (75%) believed the traveling fellowship helped them decide to pursue a career in pediatric neurosurgery, while 17 (70.8%) found that the professional connections they made were the most useful aspect of the fellowship. Fifteen (62.5%) respondents believed that the stipend of $2500 was inadequate to cover the cost of traveling and housing. CONCLUSIONS The majority of respondents are currently practicing pediatric neurosurgeons, would recommend the traveling fellowship to residents interested in neurosurgery, and believed that the experience helped them decide to pursue a career in pediatric neurosurgery. Opportunities for improvement include increasing the stipend to more appropriately fund rotations that have mostly been longer than 1 month.

Introduction and Hypothesis: New bleeding in cerebral cavernous malformations (CCM) heralds increased risk of future hemorrhage for several years, yet conventional imaging only detects new bleeding that occurred in the prior weeks. A biomarker of hemorrhage could help identifying high risk lesions. An increase of mean lesional quantitative susceptibility mapping (QSM) ≥6% on MRI has been adjudicated as reflecting new bleeding in CCM during longitudinal follow-up. However, mean lesional QSM from a single acquisition could not diagnose or prognosticate a bleed. We hypothesize that machine learning (ML) may identify diagnostic and prognostic features of bleeding within QSM maps at a single point in time. Material and Methods: Two hundred and sixty-five QSM maps of CCM lesions were acquired in 120 patients enrolled in National Institute of Health (NIH) multisite trial readiness project (NCT03652181). Each map was classified (Yes/No) in association with symptomatic hemorrhage (SH) and/or biomarker event with QSM increase ≥6% in the prior (diagnostic association) and subsequent (prognostic association) year. Twenty-eight features were extracted including 14 texture, 5 first-order statistical, as well as 3 size, shape, and morphological. Five-fold cross-validation was conducted on a support-vector machine (SVM) with linear stepwise kernel for both diagnostic and prognostic associations. Performance of individual features and composite classifiers was evaluated using student t-test ( p <0.05) with Bonferroni-correction and receiver operating characteristic (ROC) analysis, area under the curve (AUC). Results: Lesions with SH in the prior year had lower average values for sum variance (AUC=0.79, p<0.001), variance (AUC=0.79, p<0.001), and correlation (AUC=0.71, p=0.004) as compared to lesions without SH. The SVM classification method tasked with distinguishing lesions with mean QSM increase ≥6% in the prior year included recurrent selection of sum average, mean, sphericity and margin sharpness, yielding an AUC of 0.61 (p=0.02). In the prognostic cohort, no individual feature nor any SVM classification model was able to distinguish cases with a subsequent clinical bleed or biomarker event. Conclusion: This proof-of-concept suggests that ML may assist in deriving features on QSM maps acquired at a single timepoint, which reflect prior hemorrhagic activity in CCM. Further investigation is planned in larger cohorts and in conjunction with clinical trials of bleeding in CCM.

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.

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.