Emerging Pharmacologic Targets in Cerebral Cavernous Malformation and Potential Strategies to Alter the Natural History of a Difficult Disease

Abstract

erebral cavernous malformations (CCMs; cavernous angiomas, cavernomas) are low-flow, hemorrhagic vascular lesions of the central nervous system that affect 0.16% to 0.5% of the population. 1 Anatomically, they are composed of abnormal cystic vascular channels lined by a single layer of endothelial cells (ECs) with impaired tight junctions. 2 These vessels are typically arranged in compact masses with no intervening brain parenchyma, so the deriving vascular malformations are angiographically occult. They may undergo acute intracranial hemorrhage (ICH), small subclinical bleeds, or slow diapedesis of red blood cells 3 that produce a characteristic hemosiderin rim on magnetic resonance imaging. 4 In addition to causing stroke from ICH, 5 CCM can also provoke seizures, 6 headaches, and focal neurological deficits (FNDs). 5 About 20% of cases are familial and characterized by the presence of multiple lesions as opposed to sporadic CCM, which has no prevalence within families and typically presents with a single lesion. Radiation-induced cavernous malformation (RICM), a subset of sporadic CCM, can occur in patients previously treated with radiotherapy for brain tumors. Radiation-induced cavernous malformations generally occur after many years, with the time of diagnosis inversely associated with age at radiation treatment. Radiographically and histologically, they are indistinguishable from other sporadic lesions and present similar rates of symptomatic hemorrhage. However, RICM is usually diagnosed at a younger age, and patients are more likely to present with multiple lesions. 7 Cerebral cavernous malformation has a genetic basis. Its mutational landscape has been first investigated in familial forms, where predisposition to develop cavernomas is inherited through an autosomal dominant pattern with incomplete penetrance. Linkage studies allowed associating the occurrence of CCMs with loss-offunction mutations in 1 of 3 genetic loci: CCM1 (KRIT1) at chromosome 7p, 8 CCM2 (MGC4607) at 7q, and CCM3 (PDCD10) at 3q. 9 IMPORTANCE Cerebral cavernous malformations (CCMs) are vascular lesions of the brain that may lead to hemorrhage, seizures, and neurologic deficits. Most are linked to loss-of-function mutations in 1 of 3 genes, namely CCM1 (originally called KRIT1), CCM2 (MGC4607), or CCM3 (PDCD10), that can either occur as sporadic events or are inherited in an autosomal dominant pattern with incomplete penetrance. Familial forms originate from germline mutations, often have multiple intracranial lesions that grow in size and number over time, and cause an earlier and more severe presentation. Despite active preclinical research on a few pharmacologic agents, clinical translation has been slow. Open surgery and, in some cases, stereotactic radiosurgery remain the only effective treatments, but these options are limited by lesion accessibility and are associated with nonnegligible rates of morbidity and mortality. OBSERVATIONS We discuss the limits of CCM management and introduce findings from in vitro and in vivo studies ...

Cerebral Cavernous Malformation: What a Practicing Clinician Should Know

“…With clearer understanding of the genetic mechanisms underlying the familial form of CM and new laboratory techniques to study repurposing medications, several identified candidate drugs may reduce hemorrhage risk and, for those with the familial form, new lesion development. 34,76,78,89,90 Preclinical animal and in vitro data have suggested potential roles for rapamycin, 91 sorafenib, 92 sulindac (NSAID), 93 TLR4-blocking agents, 88 fasudil, [94][95][96] vitamin D, 90 tempol, 90 and simvastatin. 96 Positive effects of bevacizumab and propranolol [79][80][81][82][83] have been reported in case reports.…”

Cavernous Malformation Hemorrhagic Presentation at Diagnosis Associated with Low 25-Hydroxy-Vitamin D Level

“…Large cohorts of recently diagnosed CM patients might be helpful. In addition, as future clinical trials assessing medications for hemorrhage prevention in patients with CM evolve [19], a 2 × 2 factorial design might aid in answering the question whether supplementation is beneficial.…”

Gene expression changes associated with trajectories of psychopathology in a longitudinal cohort of children and adolescents

“…CCM2 gene (Cerebral Cavernous Malformations 2, adjusted p = 0.022, logFC = 0.331) encodes a scaffold protein that functions in the stress-activated p38 Mitogen-activated protein kinase (MAPK) signaling cascade. Mutations in this gene have been associated to cerebral cavernous malformations, which are brain vascular lesions that may lead to neurologic problems 38 . Although it has been consistently related to this disorder, studies investigating the role of this gene in other disorders are scarce.…”