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AIM To review recent developments in the understanding, diagnosis, and treatment of Sturge–Weber syndrome (SWS). METHOD Members of the Brain Vascular Malformation Consortium Sturge–Weber National Workgroup contributed their expertise, to review the literature, and present promising directions for research. RESULTS The increasing number of reports dealing with SWS over the last decade reflects progress in the diagnosis and understanding of the neurological involvement. The proliferation of centers and advocacy groups to care for patients with SWS and to stimulate research has aided the development of new insights into the clinical manifestations and the pathophysiology of neurological progression, and the development of novel hypotheses to direct future research. Many key questions remain, but the tools and networks to answer them are being developed. INTERPRETATION This review summarizes important new knowledge and presents new research directions that are likely to provide further insights, earlier diagnosis, improved treatments, and possibly, prevention of this syndrome.

BACKGROUND. Cerebral cavernous angiomas (CAs) with a symptomatic hemorrhage (CASH) have a high risk of recurrent hemorrhage and serious morbidity. METHODS. Eighteen plasma molecules with mechanistic roles in CA pathobiology were investigated in 114 patients and 12 healthy subjects. The diagnostic biomarker of a CASH in the prior year was derived as that minimizing the Akaike information criterion and validated using machine learning, and was compared with the prognostic CASH biomarker predicting bleeding in the subsequent year. Biomarkers were longitudinally followed in a subset of cases. The biomarkers were queried in the lesional neurovascular unit (NVU) transcriptome and in plasma miRNAs from CASH and non-CASH patients. RESULTS. The diagnostic CASH biomarker included a weighted combination of soluble CD14 (sCD14), VEGF, C-reactive protein (CRP), and IL-10 distinguishing CASH patients with 76% sensitivity and 80% specificity (P = 0.0003). The prognostic CASH biomarker (sCD14, VEGF, IL-1β, and sROBO-4) was confirmed to predict a bleed in the subsequent year with 83% sensitivity and 93% specificity (P = 0.001). Genes associated with diagnostic and prognostic CASH biomarkers were differentially expressed in CASH lesional NVUs. Thirteen plasma miRNAs were differentially expressed between CASH and non-CASH patients. CONCLUSION. Shared and unique biomarkers of recent symptomatic hemorrhage and of future bleeding in CA are mechanistically linked to lesional transcriptome and miRNA. The biomarkers may be applied for risk stratification in clinical trials and developed as a tool in clinical practice.