Cerebral Cavernous Malformation: What a Practicing Clinician Should Know

Abstract

Cavernous malformations (CMs) are angiographically occult, low-flow vascular malformations of the central nervous system. They are acquired lesions, with approximately 80% of patients having the sporadic form and 20% the familial form of the disease. The lesions may also develop years after radiotherapy. At the microscopic level, they consist of endothelium-lined cavities (or "caverns") containing blood of different ages. The endothelium proliferates abnormally, and tight junctions are absent or dysfunctional, resulting in leakiness of the endothelium and clinical manifestations in some patients. Cavernous malformations can be an incidental finding or can present with focal neurologic deficits, seizures, or headache, with or without associated hemorrhage. Management of the CM lesion requires knowledge of the natural history of the disease compared with the risk of surgical intervention. Surgery is often considered for symptomatic patients with lesions in a noneloquent location. Medical management is warranted for symptoms related to the CM. Research aimed at understanding the genes and signaling pathways related to CMs have provided potential drug targets, and clinical trials are underway to determine whether medications reduce the risk of future bleeding without surgery or modify the disease course. In addition, recent epidemiologic data have aided practitioners in determining how to treat comorbid conditions in patients with a potentially hemorrhagic lesion. This review provides an overview of the epidemiology, presentation, and clinical management of CMs.

Identification of a Novel CCM1 Frameshift Mutation in a Chinese Han Family With Multiple Cerebral Cavernous Malformations

“…The current study identified a novel frameshift mutation in CCM1 (c.1635delA) in a Chinese family with CCMs. In this three-generation family with 20 family members, about 30% of them (six members) have developed CCMs with multiple lesions that are the common features of FCCMs (Zafar et al, 2019;Flemming and Lanzino, 2020). The positive family history in which CCMs are present in the proband, her maternal grandmother, her mother, and her uncles indicated an autosomal dominant inheritance.…”

“…The majority of CCMs are sporadic, covering over 90% of all cases while familial CCMs (FCCMs) only account for 6-7%, which is considered as a rare disease (Moriarity et al, 1999a;Batra et al, 2009;Spiegler et al, 2018;Zafar et al, 2019). However, less than 20% of patients with sporadic CCMs have multiple lesions (Moriarity et al, 1999b;Dammann et al, 2017;Flemming and Lanzino, 2020), whereas over 50% of FCCMs cause multiple CCM lesions, which will increase the risk of developing epilepsy and intracranial hemorrhage (Russo et al, 2017;Zafar et al, 2019).…”

“…Most patients developed CCMs at their 30s to 40s, but a quarter of CCMs take place in childhood and even during infancy (Al-Holou et al, 2012;Brinjikji et al, 2017) and thus dramatically impact on the quality of the patients' life. The clinical manifestations of CCMs include epilepsy, headache, intracranial hemorrhage and focal neurological dysfunction (Denier et al, 2004;Al-Shahi Salman et al, 2012;Flemming and Lanzino, 2020). The clinical pathology has shown that within the CCM lesions, these blood vessels are often enlarged and lack tight endothelial cell junctions and vesicular smooth muscles.…”

Inactivation of Cerebral Cavernous Malformation Genes Results in Accumulation of von Willebrand Factor and Redistribution of Weibel-Palade Bodies in Endothelial Cells

“…Since the first reports of disease-causing CCM1 variants in familial CCM cases (Laberge-le Couteulx et al, 1999;Sahoo et al, 1999), we have learned a lot about CCM pathogenesis and the endothelial dysfunction in cavernous lesions (Maddaluno et al, 2013;Cuttano et al, 2016;Zhou et al, 2016;Detter et al, 2018;Malinverno et al, 2019;Hong et al, 2020;Ren et al, 2021). A first expert consensus guideline and clinical recommendations for CCM management have been published in recent years (Akers et al, 2017;Flemming and Lanzino, 2020). However, there are still no effective drugs that would prevent cavernoma formation or CCM bleeding.…”

Non-autonomous effects of CCM genes loss

“…Symptoms may occur at any age, although the typical age of onset is between the second and fifth decade of life and without sex predominance, even though the available data are conflicting. Moreover, the majority of CCM lesions remain clinically and biologically quiescent during the most of the host's lifetime [4][5][6] . To date, diagnosis is made only by magnetic resonance imaging (MRI), and it is mainly possible only when lesions become symptomatic [3] .…”