Synopsis of Guidelines for the Clinical Management of Cerebral Cavernous Malformations: Consensus Recommendations Based on Systematic Literature Review by the Angioma Alliance Scientific Advisory Board Clinical Experts Panel

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.

Cerebral Cavernous Malformations: An Update on Prevalence, Molecular Genetic Analyses, and Genetic Counselling

“…The haemorrhage rate per patient-year has been reported to be significantly lower in incidentally discovered groups when compared to symptomatic groups [Washington et al, 2010;Al-Holou et al, 2012;Al-Shahi Salman et al, 2012;Gross et al, 2016;Horne et al, 2016;Akers et al, 2017]. In a single-centre cohort of 107 individuals with CCM as an incidental finding, the only patient in whom a prospective haemorrhage was definitively related to the cavernous malformation was in fact diagnosed as having a familial form of CCM.…”

“…Since mutational hot spots in the 3 genes cannot be defined ( Fig. 2 ), a stepwise screening approach is generally not reasonable any more unless an individual has Hispanic ancestry of Mexican or southwest US-American descent [Akers et al, 2017] or originates from the Ashkenazi-Jewish population [Gallione et al, 2011]. Therefore, CCM molecular genetic analyses currently include targeted capture of all coding exons and exon/intron junctions followed by massively parallel sequencing and deletion/duplication Mutations listed as low-confidence variants in the gnomAD browser have not been included.…”

“…The mutation detection rate in a diagnostic context is highly dependent on the inclusion criteria which have been specified in Akers et al [2017] and the scope of the analysis. Pathogenic variants can be identified in 87-98% of all cases with a positive family history [Denier et al, 2006;Stahl et al, 2008;Cigoli et al, 2014;Spiegler et al 2014].…”

“…However, the guidelines published by Akers et al in 2017 ( Table 2 ) recommend to include only those that neither present with an associated developmental venous anomaly nor with a history of brain radiation as this is a known risk factor for CCM formation [Heckl et al, 2002;Nimjee et al, 2006]. Following these recommendations, mutation detection rates higher than 75% appear to be realistic [Akers et al, 2017].…”

Combinations of Multiple Neuroimaging Markers using Logistic Regression for Auxiliary Diagnosis of Alzheimer Disease and Mild Cognitive Impairment

“…At present, several analytic methods have been used in the joint analysis of multiple data sources [15, 16, 23]. The receiver-operating characteristic (ROC) curve analysis and the area under the curve (AUC) are often utilized to characterize the performance of a given index in distinguishing AD or MCI from normal controls (NC) [24, 25].…”