Effect of Simvastatin on Permeability in Cerebral Cavernous Malformation Type 1 Patients: Results from a Pilot Small Randomized Controlled Clinical Trial

Abstract

Cerebral cavernous malformations (CCMs) are low-flow vascular malformations that can occur in sporadic or familial forms, with familial CCM syndrome caused by an inherited mutation in one of the three known CCM genes [1–3]. The clinical course is highly variable, particularly in familial CCM patients where CCMs can number into hundreds and patients can range from being asymptomatic to having seizures, headaches, focal neurological deficits, intracranial hemorrhage, or death. Although CCMs can be associated with significant morbidity, treatment options are generally limited to surgical resection of selected symptomatic lesions. Ideally, a medical therapy would be able to prevent the formation of new CCMs and decrease the risk of hemorrhage and growth of CCMs. Statins have been identified as a potential therapy for CCMs as they have been shown to prevent CCM formation and decrease permeability in animal models through Rho kinase inhibition [4–8]. Since CCMs form, enlarge, and hemorrhage at a relatively low rate, a therapeutic trial monitoring hemorrhage or formation and enlargement of CCMs would require many years, a large number of patients, and huge expense [1, 2, 9]. Dynamic contrast-enhanced perfusion MRI (DCEMRI) is a T1-based MRI technique that has demonstrated the capacity to measure low-level permeability within CCMs and has been identified as a potential quantitative biomarker [10–13]. Permeability of CCMs as measured by DCEMRI would be an ideal biomarker to assess therapeutic effects of drugs on CCMs. We initiated a small, prospective, randomized, controlled trial as a pilot study to test the feasibility of using DCEMRI to evaluate permeability in CCM patients treated with simvastatin and control CCM patients not treated with simvastatin; we aimed to evaluate feasibility, safety, and the exploratory hypothesis that simvastatin treatment would alter permeability as measured by DCEMRI. Twelve patients with CCM1 underwent informed consent for this institutional review board-approved study and were randomized to receive simvastatin (n = 6) or be in the control group (n = 6). Inclusion criteria for the study were diagnosis of CCM1 Common Hispanic Mutation and willingness to travel for 5 visits over 3 months; exclusion criteria were incarceration, inability to pass MRI safety screening, liver or kidney dysfunction, allergy to gadolinium or statins, currently taking statins or within last 6 months, consumption of large amounts of alcohol, elevated creatine kinase, triglycerides, or liver enzymes, or taking potentially interacting medications. The treatment arm patients received 20 mg of simvastatin daily by mouth for the first month and then 40 mg of simvastatin by mouth for the second and third months with laboratory monitoring. Patients underwent 3-T DCEMRI at baseline before treatment and again after 3 months. CCMs and normalappearing white matter were segmented from anatomic images, and CCM and normal-appearing white matter mean permeability (Ki) were calculated for each study [10]. A total of 10 pairs of DCEMRI studies were of adequate quality for * Marc C Mabray [email protected]