Fam, Maged D

Abstract BACKGROUND More than a million Americans harbor a cerebral cavernous angioma (CA), and those who suffer a prior symptomatic hemorrhage have an exceptionally high rebleeding risk. Preclinical studies show that atorvastatin blunts CA lesion development and hemorrhage through inhibiting RhoA kinase (ROCK), suggesting it may confer a therapeutic benefit. OBJECTIVE To evaluate whether atorvastatin produces a difference compared to placebo in lesional iron deposition as assessed by quantitative susceptibility mapping (QSM) on magnetic resonance imaging in CAs that have demonstrated a symptomatic hemorrhage in the prior year. Secondary aims shall assess effects on vascular permeability, ROCK activity in peripheral leukocytes, signal effects on clinical outcomes, adverse events, and prespecified subgroups. METHODS The phase I/IIa placebo-controlled, double-blinded, single-site clinical trial aims to enroll 80 subjects randomized 1-1 to atorvastatin (starting dose 80 mg PO daily) or placebo. Dosing shall continue for 24-mo or until reaching a safety endpoint. EXPECTED OUTCOMES The trial is powered to detect an absolute difference of 20% in the mean percent change in lesional QSM per year (2-tailed, power 0.9, alpha 0.05). A decrease in QSM change would be a signal of potential benefit, and an increase would signal a safety concern with the drug. DISCUSSION With firm mechanistic rationale, rigorous preclinical discoveries, and biomarker validations, the trial shall explore a proof of concept effect of a widely used repurposed drug in stabilizing CAs after a symptomatic hemorrhage. This will be the first clinical trial of a drug aimed at altering rebleeding in CA.

Abstract Dural membrane is an important anatomic structure that surrounds and protects the entire central nervous system. Physical properties of the dura have many pathophysiological and therapeutic implications in cranial surgery, especially skull base disorders. The aim of this study is to investigate variation in skull base dural thickness and correlation with different demographic parameters. At the time of autopsy, the petrous apex dura with the underlying bone of 20 cadavers was harvested. Dural thickness was independently measured by two pathologists at the thinnest and thickest segments in the specimen. Correlational analyses were then performed to compare dural thickness with gender, age, neck circumference, height, weight, and body mass index (BMI). Mean, minimum, and maximum skull base dural thickness in our study was 0.36, 0.27, and 0.46 mm, respectively. Age demonstrated a negative correlation with dural thickness with significantly thinner dura in the older subjects, p = 0.01. There was a trend toward thinner dura in females that approached statistical significance, p = 0.06. No strong correlation could be found with body weight, height, neck circumference, or BMI. Our findings show a considerable intersubject and intrasubject variability in skull base dural thickness. Some demographic parameters also seem to impact dural thickness. Additional histological studies are needed for better understanding of the pathophysiological mechanisms pertaining to the tensile properties of the dural membrane.