Predictors of Initial Presentation with Hemorrhage in Patients with Cavernous Malformations

Flemming, Kelly D.; Kumar, Shivram; Brown, Robert D.; Lanzino, Giuseppe

doi:10.1016/j.wneu.2019.09.161

Cited by 26 publications

(37 citation statements)

References 24 publications

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“…Importantly, we notice that the inhibition of COX-2 in the chronic CCM animal model results not only in a decrease in CCM lesions' density but also in GFAPimmunoreactivity, suggesting that amelioration of lesion genesis counterparts astrocyte activity in the lesions. In line with these results, a recent retrospective cohort study reported that the use of NSAIDs was correlated with lower risk of hemorrhage among patients affected by CCMs (92).…”

Section: Discussionsupporting

confidence: 65%

Astrocytes propel neurovascular dysfunction during cerebral cavernous malformation lesion formation

Lopez-Ramirez¹,

Lai²,

Soliman³

et al. 2021

Journal of Clinical Investigation

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Cerebral cavernous malformations (CCMs) are common neurovascular lesions caused by lossof-function mutations in one of three genes, including KRIT1 (CCM1), CCM2, and PDCD10 (CCM3), and generally regarded as an endothelial cell-autonomous disease. Here we reported that proliferative astrocytes played a critical role in CCM pathogenesis by serving as a major source of VEGF during CCM lesion formation. An increase in astrocyte VEGF synthesis is driven by endothelial nitric oxide (NO) generated as a consequence of KLF2 and KLF4-dependent elevation of eNOS in CCM endothelium. The increased brain endothelial production of NO stabilized HIF-1a in astrocytes, resulting in increased VEGF production and expression of a "hypoxic" program under normoxic conditions. We showed that the upregulation of cyclooxygenase-2 (COX-2), a direct HIF-1a target gene and a known component of the hypoxic program, contributed to the development of CCM lesions because the administration of a COX-2 inhibitor significantly prevented the progression of CCM lesions. Thus, non-cell-autonomous crosstalk between CCM endothelium and astrocytes propels vascular lesion development, and components of the hypoxic program represent potential therapeutic targets for CCMs.

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Section: Discussionsupporting

confidence: 65%

Astrocytes propel neurovascular dysfunction during cerebral cavernous malformation lesion formation

Lopez-Ramirez¹,

Lai²,

Soliman³

et al. 2021

Journal of Clinical Investigation

View full text Add to dashboard Cite

show abstract

Section: Discussionsupporting

confidence: 65%

Non cell-autonomous effect of astrocytes on cerebral cavernous malformations

Ma¹,

Si²,

Hale³

et al. 2021

Preprint

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Cerebral cavernous malformations (CCMs) are common neurovascular lesions caused by loss-of-function mutations in one of three genes, including KRIT1 (CCM1), CCM2, and PDCD10 (CCM3), and generally regarded as an endothelial cell-autonomous disease. Here we report that proliferative astrocytes play a critical role in CCM pathogenesis by serving as a major source of VEGF during CCM lesion formation. An increase in astrocyte VEGF synthesis is driven by endothelial nitric oxide (NO) generated as a consequence of KLF2 and KLF4-dependent elevation of eNOS in CCM endothelium. The increased brain endothelial production of NO stabilizes HIF-1α in astrocytes, resulting in increased VEGF production and expression of a “hypoxic” program under normoxic conditions. We show that the upregulation of cyclooxygenase-2 (COX-2), a direct HIF-1α target gene and a known component of the hypoxic program, contributes to the development of CCM lesions because the administration of a COX-2 inhibitor significantly prevents progression of CCM lesions. Thus, non-cell-autonomous crosstalk between CCM endothelium and astrocytes propels vascular lesion development, and components of the hypoxic program represent potential therapeutic targets for CCMs.

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“…34 In a large cohort of prospectively recruited patients (n¼202) who underwent structured interview, questionnaire, and medical record and MRI review, 37.1% presented with acute clinical hemorrhage, 6.5% with focal neurologic deficit without hemorrhage, 14.8% with seizures without hemorrhage, and 40.6% with an incidental finding. 43 Unlike arterial pathology (eg, arteriovenous malformation or aneurysm), patients with CM presenting with hemorrhage most commonly progressed over 2 to 30 or more days after the new symptoms first appeared. Patients with a brainstem-located CM were more likely to present with hemorrhage.…”

Section: Clinical Presentationmentioning

confidence: 99%

Cerebral Cavernous Malformation: What a Practicing Clinician Should Know

Flemming

Lanzino

2020

Mayo Clinic Proceedings

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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.

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Predictors of Initial Presentation with Hemorrhage in Patients with Cavernous Malformations

Cited by 26 publications

References 24 publications

Astrocytes propel neurovascular dysfunction during cerebral cavernous malformation lesion formation

Astrocytes propel neurovascular dysfunction during cerebral cavernous malformation lesion formation

Non cell-autonomous effect of astrocytes on cerebral cavernous malformations

Cerebral Cavernous Malformation: What a Practicing Clinician Should Know

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