Hart, Blaine L.

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.

Abstract BACKGROUND: Despite many publications about cerebral cavernous malformations (CCMs), controversy remains regarding diagnostic and management strategies. OBJECTIVE: To develop guidelines for CCM management. METHODS: The Angioma Alliance (www.angioma.org), the patient support group in the United States advocating on behalf of patients and research in CCM, convened a multidisciplinary writing group comprising expert CCM clinicians to help summarize the existing literature related to the clinical care of CCM, focusing on 5 topics: (1) epidemiology and natural history, (2) genetic testing and counseling, (3) diagnostic criteria and radiology standards, (4) neurosurgical considerations, and (5) neurological considerations. The group reviewed literature, rated evidence, developed recommendations, and established consensus, controversies, and knowledge gaps according to a prespecified protocol. RESULTS: Of 1270 publications published between January 1, 1983 and September 31, 2014, we selected 98 based on methodological criteria, and identified 38 additional recent or relevant publications. Topic authors used these publications to summarize current knowledge and arrive at 23 consensus management recommendations, which we rated by class (size of effect) and level (estimate of certainty) according to the American Heart Association/American Stroke Association criteria. No recommendation was level A (because of the absence of randomized controlled trials), 11 (48%) were level B, and 12 (52%) were level C. Recommendations were class I in 8 (35%), class II in 10 (43%), and class III in 5 (22%). CONCLUSION: Current evidence supports recommendations for the management of CCM, but their generally low levels and classes mandate further research to better inform clinical practice and update these recommendations. The complete recommendations document, including the criteria for selecting reference citations, a more detailed justification of the respective recommendations, and a summary of controversies and knowledge gaps, was similarly peer reviewed and is available on line www.angioma.org/CCMGuidelines.