Infratentorial Developmental Venous Abnormalities and Inflammation Increase Odds of Sporadic Cavernous Malformation

doi:10.1016/j.jstrokecerebrovasdis.2019.02.025

Journal of Stroke and Cerebrovascular Diseases

Volume 28, Issue 6, June 2019, Pages 1662-1667

https://doi.org/10.1016/j.jstrokecerebrovasdis.2019.02.025 Get rights and content

Abstract

Goal: Sporadic brain cavernous malformations commonly correlate with developmental venous anomalies; however, developmental venous anomalies may exist without cavernous malformations. Infratentorial location and specific angioarchitectural features of the developmental venous anomaly increase the odds of a concomitant malformation. Animal data also suggest chronic inflammatory disease, oxidative stress, and angiogenesis promote cavernous malformation development. We sought to determine potential clinical and radiologic factors promoting development of sporadic cavernous malformations. Methods: One hundred and forty-five patients with sporadic, nonradiation-induced brain cavernous malformations (63 with radiologic-apparent and 82 with radiologic-occult developmental venous anomalies) were compared to developmental venous anomaly controls without associated malformation. Data collection included demographic information, comorbidities, medications at diagnosis, and location of the developmental venous anomaly and/or malformation. Logistic regression with likelihood ratios, odds ratios and 95% confidence intervals were calculated comparing malformation cases with controls. A similar analysis compared malformations with radiologic-apparent anomalies to controls. Results: Compared to controls, cases were more likely to have had a major infectious illness (10.3% versus 2.3%; P = .0003 and/or chronic inflammatory disease (31.7% versus 21.3%; P = .0184) prior to diagnostic magnetic resonance imaging. Infratentorial location was more common in cavernous malformation cases (31.7% versus 15.7% controls; P ≤ .0001) with similar findings in cavernous malformation with radiologic-apparent developmental venous anomalies versus controls. Conclusions: Infratentorial developmental venous anomalies location, major infectious illness, and chronic inflammatory disorders increase the odds of sporadic cavernous malformation formation. Inflammation may promote local thrombosis of developmental venous anomalies, trigger angiogenic response through increased vascular permeability, or promote cavernous malformation through Toll-like receptor 4.

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 Medicine
Citation 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].
Cerebral Cavernous Malformation (CCM) is a cerebrovascular disease of genetic origin affecting 0.5% of the population and characterized by abnormally enlarged and leaky capillaries that predispose to seizures, neurological deficits, and intracerebral hemorrhage (ICH). CCM occurs sporadically or is inherited as dominant condition with incomplete penetrance and highly variable expressivity. Three disease genes have been identified: KRIT1 (CCM1), CCM2 and CCM3. Previous results demonstrated that loss-of-function mutations of CCM genes cause pleiotropic effects, including defective autophagy, altered reactive oxygen species (ROS) homeostasis, and enhanced sensitivity to oxidative stress and inflammatory events, suggesting a novel unifying pathogenetic mechanism, and raising the possibility that CCM disease onset and severity are influenced by the presence of susceptibility and modifier genes. Consistently, genome-wide association studies (GWAS) in large and homogeneous cohorts of patients sharing the familial form of CCM disease and identical mutations in CCM genes have led to the discovery of distinct genetic modifiers of major disease severity phenotypes, such as development of numerous and large CCM lesions, and susceptibility to ICH.
This review deals with the identification of genetic modifiers with a significant impact on inter-individual variability in CCM disease onset and severity, including highly polymorphic genes involved in oxidative stress, inflammatory and immune responses, such as cytochrome P450 monooxygenases (CYP), matrix metalloproteinases (MMP), and Toll-like receptors (TLR), pointing to their emerging prognostic value, and opening up new perspectives for risk stratification and personalized medicine strategies.
Evolution of Developmental Venous Anomalies in the Setting of a Torcular Dural Arteriovenous Fistula and Cerebrofacial Venous Metameric Syndrome
2020, World Neurosurgery
Citation 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.
We describe evolution of a developmental venous anomaly (DVA) over time in a patient with a complex intracranial vascular malformation.
A 26-year-old male patient initially presented with a scalp vascular malformation and was later diagnosed to have a torcular dural arteriovenous fistula resembling a dural sinus malformation. The dural fistula increased in size over 4 years. The dural fistula also was associated with multiple complex developmental venous anomalies draining the bilateral cerebral hemispheres and cerebellum. The DVA was only faintly demonstrated on the baseline magnetic resonance imaging but appeared to increase in size and extent over time as the dural arteriovenous fistula developed more aggressive angioarchitecture features. In addition to the evolution manifestation of the DVAs, the patient developed multiple de novo cavernous malformations in the venous radicles of the DVA. Increased venous hypertension in the superficial venous system from the dural fistula likely resulted in growth of the DVAs, as they served as the primary means of venous drainage for the bilateral cerebral hemispheres. The patient also had reopening of the persistent falcine sinus, which was not present at baseline.
This would be the first reported case of growth or evolution of a DVA in association with a dural arteriovenous fistula in an adult patient and highlights the dynamic nature of both the medullary venous and dural venous sinuses of the cerebral venous system, even into adulthood.
Cerebral Cavernous Malformation: What a Practicing Clinician Should Know
2020, Mayo Clinic Proceedings
Citation 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.
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.
Predictors of Initial Presentation with Hemorrhage in Patients with Cavernous Malformations
2020, World Neurosurgery
Citation 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.
Cavernous malformations (CMs) are low-flow vascular malformations of the central nervous system which are incidental or present with hemorrhage, seizures, or focal neurologic deficit (FND). Little is known about the time course of symptoms and the predictors of initial hemorrhagic presentation.
Beginning in 2015, consecutive patients with radiologically confirmed CMs were recruited and completed a structured interview and written survey at baseline. Medical records and magnetic resonance imaging studies were reviewed. Data collected included the following: comorbid conditions, select medication use, and location of CMs. Logistic-regression models determined predictors of initial presentation with hemorrhage.
Of 202 patients, 58.4% were women (average age at diagnosis, 43.7 ± 16.5 years). Of the patients, 37.1%, 6.5%, and 14.8% presented with hemorrhage, FND, and seizures, respectively. CM was an incidental finding in 40.6%. Most patients presenting with hemorrhage (66.7%) deteriorated over 2–30 days after symptom onset. Brainstem location correlated with a higher likelihood of initial presentation with hemorrhage. Aspirin use and nonsteroidal anti-inflammatory drug use were more common in patients with CMs who did not present with hemorrhage. The effect of estrogen and aspirin was stronger in the sporadic compared with the familial form of CMs. In women, estrogen use increased the likelihood of presenting with hemorrhage.
This prospective cohort study confirms brainstem location increases the likelihood of presenting with hemorrhage, but also supports a potential role of select medications on the initial clinical presentation of CMs. Further data from combined cohorts may aid in determining whether the influence of medications is different in familial versus sporadic form CMs.
Intraaxial and Extraaxial Cavernous Malformation with Venous Linkage: Immune Cellular Inflammation Associated with Aggressiveness
2019, World Neurosurgery
Citation 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.
Intraorbital and intracerebral cavernous malformation (CM) lesions are considered independent entities. Purely cerebral CMs have variable biology with recent evidence depicting inflammation as an important player and a risk factor for aggressiveness. We describe a case of concomitant left intraaxial and extraaxial CMs, linked by the ipsilateral basal vein, where the extraaxial component has developed an aggressive behavior.
A 35-year-old female patient presented with a rapid and progressive exophthalmos and loss of vision on the left eye. Cranial magnetic resonance and angiography examinations demonstrated a left craniofacial CM and large intraorbital component. The lesion was connected through a large basal vein to a cerebral intraventricular CM. Transconjunctival resection showed typical findings of CM. A complete histopathology and immunostaining analysis was performed and revealed a clear acute lymphomononuclear reaction with a predominant immune cellular inflammation.
A case of intraorbital and extracranial cavernomatous mass, connected to a cerebral intraventricular CM through a large basal vein, has presented with an aggressive course. A complete histopathologic and immunohistochemical analysis of the orbital mass has pictured a clear immune-cellular inflammatory reaction adding to the amounting evidence of association between inflammation and site aggressiveness in the setting of CMs.
Symptomatic Cavernous Malformation Presenting with Seizure without Hemorrhage: Analysis of Factors Influencing Clinical Presentation
2019, World Neurosurgery
Citation 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
Supratentorial cavernous malformations (CMs) can be epileptogenic lesions. However, little is known about clinical comorbidities, medication use, and radiologic features that predict a first seizure presentation without associated CM hemorrhage.
We queried a prospective registry of consecutive patients with CM established in January 2015. Data regarding clinical presentation, comorbid conditions, daily medication use, and radiologic CM characteristics were collected. Univariate and multivariate regression analysis was performed assessing variables for presentation with seizure without hemorrhage with P values, odds ratios, and 95% confidence intervals reported.
Of 202 patients, 58.4% were women, and the average age at diagnosis was 43.7 ± 16.5 years. Of the patients, 59.4% were symptomatic. In 40.6%, the CM was an incidental finding. Of the 30 patients who presented with a first-time seizure without concomitant hemorrhage, the mean age at diagnosis was 38.4 ± 14.6 years, and 56.7% were women. Compared with incidental CM, patients with seizure without hemorrhage were younger, had a cortically based, supratentorial lesion, and were less likely to have chronic inflammatory disease or to use aspirin, vitamin D, or statin. Compared with other supratentorial lesions, patients with seizure without hemorrhage more commonly had a temporal lobe CM.
These prospective data provide possible clues to radiologic factors, clinical comorbidities, and medication influences on seizure presentation in patients with CM. Further multicenter studies would be helpful to determine if disease-modifying agents in addition to epileptic medications or surgery might be helpful.

View all citing articles on Scopus

: 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.

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Infratentorial Developmental Venous Abnormalities and Inflammation Increase Odds of Sporadic Cavernous Malformation

Abstract

Introduction

Section snippets

CM Patient Selection

Results

Discussion

Int J Biochem Cell Biol

Clinical management of cavernous malformations

Curr Cardiol Rep

Developmental venous anomalies: current concepts and implications for management

Neurosurgery

The venous angioarchitecture of sporadic cerebral cavernous malformations: a susceptibility weighted imaging study at 7 T MRI

J Neurol Neurosurg Psychiatry

Cavernous malformations of the brainstem: experience with 100 patients

J Neurosurg

Correlation of the venous angioarchitecture of multiple cerebral cavernous malformations with familial or sporadic disease: a susceptibility-weighted imaging study with 7-Tesla MRI

J Neurosurg

The putative role of the venous system in the genesis of vascular malformations

Neurosurg Focus

The association of venous developmental anomalies and cavernous malformations: pathophysiological, diagnostic, and surgical considerations

Neurosurg Focus

Hemodynamic effects of developmental venous anomalies with and without cavernous malformations

AJNR Am J Neuroradiol

Mixed vascular malformations of the brain: clinical and pathogenetic considerations

Neurosurgery

Expression of angiogenic factors and structural proteins in the central nervous system vascular malformations

Neurosurgery

Cryptic vascular malformations

Clin Neurosurg

The association between cerebral developmental venous anomaly and concomitant cavernous malformation: an observational study using magnetic resonance imaging

BMC Neurol