Infratentorial Developmental Venous Abnormalities and Inflammation Increase Odds of Sporadic Cavernous Malformation
Introduction
Cavernous malformations (CMs) are angiographically occult vascular malformations that may form in the brain or spinal cord. Pathologically they consist of endothelial-lined caverns lacking normally formed endothelial tight junctions.1
CM may be acquired and sporadic or familial. In the sporadic form, patients typically have a single CM lesion with an associated developmental venous anomaly (DVA). In approximately 10%-30% of CM patients, the DVA is visible on standard magnetic resonance imaging (MRI) sequences.2 However, surgical series and 7-T MRI data suggest that every sporadic brain CM has an associated DVA.3, 4, 5
Current opinion is that the DVA causes the CM to form sometime during life,2 and there are well-documented cases of CMs developing adjacent to previously known DVAs.6, 7 Some have hypothesized that the DVA causes venous hypertension, and red-cell diapedesis occurs in the local tissue with resultant angiogenic response.2, 6,8, 9, 10 Others hypothesize that local hypoxia due to venous hypertension triggers angiogenesis.11 It is not clear why some patients with DVA develop coexistent cavernous malformations while others do not. Proposed radiologic risk factors include infratentorial location, stenosis of the dominant collecting vein, venous outflow obstruction, tortuosity of the collecting vein, and the multiplicity of medullary veins.2, 8,12, 13, 14 Less data are available on clinical factors that also may play a role.
Animal models based on the familial form of CM demonstrate that factors other than the abnormal gene are necessary for lesion development. Hypothesized factors include oxidative stress, inflammation, and abnormal angiogenesis.15 There are no animal models of the sporadic type of CM. We hypothesize that the inflammation or modifiers of inflammation may influence patients with DVA to develop concomitant CM.
We aimed to determine whether acute and chronic inflammatory conditions, select medication use, and lesion location are more common in patients with sporadic, brain CM versus DVA controls without concomitant CM in a case-control design.
Section snippets
CM Patient Selection
An IRB-approved ongoing prospective registry of consecutive patients with CM seen at our institution has been kept since 2015. All patients or their authorized representatives provided written consent for the use of their medical information for research purposes. Since familial CMs are not associated with DVAs, we excluded patients with familial CMs. We further excluded those CMs felt to be caused by radiation and those located in the spinal cord. Because all sporadic brain CMs presumptively
Results
We identified 145 CM cases (63 with apparent radiologic DVA and 82 with occult radiologic DVA) and 300 DVA controls. Indication for DVA control group MRI included neoplastic evaluation (26.7%), seizure (9.7%), headache (17.3%), dizziness/ataxia/vertigo (7.3%), acquired brain disorder (10.7%), degenerative brain disorders or encephalopathy (6.3%), neurologic symptoms/exam signs (13.0%), and noncancer systemic evaluation (9.0%).
Clinical and radiologic information is presented in Table 2. The
Discussion
It is known that patients with DVA may develop CM, but the factors leading to CM formation from a pre-existing DVA are a matter of speculation. While some have suggested the location and venous angioarchitecture may play a role,2, 8,12, 13, 14,21 potential concomitant clinical factors are largely unknown. Here, for the first time, we report a higher incidence of pre-existing inflammatory conditions in patients with sporadic CMs than in an age-matched DVA control group without CM. This suggests
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Cited by (20)
Polymorphisms in genes related to oxidative stress and inflammation: Emerging links with the pathogenesis and severity of Cerebral Cavernous Malformation disease
2021, Free Radical Biology and MedicineCitation Excerpt :Notably, further support was also provided by a clinical study showing that the coexistence of genetic variants in genes related to inflammation and oxidative stress, including TLR4 (rs10759930) and SOD2 (rs4880), may indeed act as modifier factors that influence the heterogeneity of clinical manifestations among individuals with familial CCM, suggesting prognostic and therapeutic implications [263]. Moreover, consistent with the possibility that a major contribution of oxidative stress and inflammation to CCM disease pathogenesis and severity occurs also in sporadic CCM cases, another recent clinical study showed that infectious illness and chronic inflammatory disorders increase significantly the odds of sporadic CCM formation [264]. In this context, it is intriguing that TLR-mediated inflammation was shown to be attenuated by a vitamin D receptor (VDR) signaling that enhances the fundamental negative feedback inhibition mechanism involved in the control of duration and intensity of inflammatory responses [265,266].
Evolution of Developmental Venous Anomalies in the Setting of a Torcular Dural Arteriovenous Fistula and Cerebrofacial Venous Metameric Syndrome
2020, World NeurosurgeryCitation Excerpt :A similar mechanism was noted in a previously reported case.11 The association between cavernous malformations and DVAs is well known, with some studies showing that up to 100% of sporadic cavernous malformations are associated with DVAs.3,4,8,12 The fact that these cavernous malformations developed along the same time course as the dAVF became more aggressive likely confirms the theory that DVA-associated cavernous malformations form in response to venous hypertension.
Cerebral Cavernous Malformation: What a Practicing Clinician Should Know
2020, Mayo Clinic ProceedingsCitation Excerpt :Polymorphisms in inflammatory and immune-response pathways predicted CM lesion burden in patients with CCM type 1.86 In another study, patients with sporadic CMs were more likely to have a chronic inflammatory disease compared with patients with a DVA without a CM.87 Recently, investigators found a potential role for the gut microbiome in the genesis of CM.
Predictors of Initial Presentation with Hemorrhage in Patients with Cavernous Malformations
2020, World NeurosurgeryCitation Excerpt :Demographic data, comorbid conditions, medications at diagnosis, and ongoing use of medications were all collected from in-person interviews, medical record review, and an initial questionnaire. Specific comorbid conditions of interest included the following: history of a major infectious illness (requiring hospitalization), venous clotting disorder (e.g., deep venous thrombosis), chronic inflammatory conditions,14 neoplasm, and self-reported concussion. Specific medications of interest included the use of the following at first CM symptoms: aspirin, any antithrombotic (warfarin, direct oral anticoagulants, heparin, clopidogrel, and ticagrelor), nonsteroidal anti-inflammatory drugs (NSAIDs), vitamin D supplementation, statin, fish oil, vitamin E, and serotonin reuptake inhibitors.
Intraaxial and Extraaxial Cavernous Malformation with Venous Linkage: Immune Cellular Inflammation Associated with Aggressiveness
2019, World NeurosurgeryCitation Excerpt :Although developmental venous anomalies (DVA) associated with parenchymal cavernous lesions are well known and magnetic resonance imaging 7 Tesla studies suggesting that every sporadic CM has an associated DVA,10 the related pathogenesis is not yet defined. Inflammatory hypothesis has been recently discussed as a possible mechanism for the genesis of cavernous lesion next to DVAs, raising concerns about a tendency of higher aggressiveness in associated lesions.11,12 We present a rare case of a clinically aggressive orbital CM linked to a quiescent intracerebral, intraventricular CM by an enlarged ipsilateral basal vein (a “DVA-like” connection), depicting an extensive in situ immune-cellular inflammatory reaction.
Symptomatic Cavernous Malformation Presenting with Seizure without Hemorrhage: Analysis of Factors Influencing Clinical Presentation
2019, World NeurosurgeryCitation Excerpt :Although some studies have shown multiple lesions or the familial form to present more commonly with seizure,1 we did not find this to be true in our cohort. Our group previously found that chronic inflammatory disorders increased the risk of sporadic CM formation compared with DVA control subjects.18 Animal data also support a role for inflammatory disease in increasing lesion burden and disease severity.19
This publication was supported by Grant Number UL1 TR002377 from the National Center for Advancing Translational Sciences (NCATS). Its contents are solely the responsibility of the authors and do not necessarily represent the official views of the NIH.