Molecular Biomarkers and Drug Targets in Brain Arteriovenous and Cavernous Malformations: Where Are We?

Stroke ◽  
2021 ◽  
Author(s):  
Vani Venugopal ◽  
S. Sumi
Keyword(s):  
Noncoding Rna ◽  
Drug Targets ◽  
Vascular Malformations ◽  
Phenotypic Variability ◽  
Abnormal Development ◽  
Neurological Deficits ◽  
Cavernous Malformations ◽  
Technological Advances ◽  
Predictive And Prognostic Biomarker ◽  
The Brain

Vascular malformations of the brain (VMB) comprise abnormal development of blood vessels. A small fraction of VMBs causes hemorrhages with neurological morbidity and risk of mortality in patients. Most often, they are symptomatically silent and are detected at advanced stages of disease progression. The most common forms of VMBs are arteriovenous and cavernous malformations in the brain. Radiopathological features of these diseases are complex with high phenotypic variability. Early detection of these malformations followed by preclusion of severe neurological deficits such as hemorrhage and stroke is crucial in the clinical management of patients with VMBs. The technological advances in high-throughput omics platforms have currently infused a zest in translational research in VMBs. Besides finding novel biomarkers and therapeutic targets, these studies have withal contributed significantly to the understanding of the etiopathogenesis of VMBs. Here we discuss the recent advances in predictive and prognostic biomarker research in sporadic and familial arteriovenous malformations as well as cerebral cavernous malformations. Furthermore, we analyze the clinical applicability of protein and noncoding RNA-based molecular-targeted therapies which may have a potentially key role in disease management.

scholarly journals Management of Cerebral Cavernous Malformations: From Diagnosis to Treatment

2015 ◽  
Vol 2015 ◽  
pp. 1-8 ◽  
Author(s):  
Nikolaos Mouchtouris ◽  
Nohra Chalouhi ◽  
Ameet Chitale ◽  
Robert M. Starke ◽  
Stavropoula I. Tjoumakaris ◽  
...  
Keyword(s):  
Clinical Presentation ◽  
Vascular Malformations ◽  
Imaging Techniques ◽  
Neurological Deficits ◽  
Cerebral Cavernous Malformations ◽  
Cavernous Malformations ◽  
Microsurgical Resection ◽  
Different Characteristics ◽  
The Brain ◽  
Methods Of Treatment

Cerebral cavernous malformations are the most common vascular malformations and can be found in many locations in the brain. If left untreated, cavernomas may lead to intracerebral hemorrhage, seizures, focal neurological deficits, or headaches. As they are angiographically occult, their diagnosis relies on various MR imaging techniques, which detect different characteristics of the lesions as well as aiding in planning the surgical treatment. The clinical presentation and the location of the lesion are the most important factors involved in determining the optimal course of treatment of cavernomas. We concisely review the literature and discuss the advantages and limitations of each of the three available methods of treatment—microsurgical resection, stereotactic radiosurgery, and conservative management—depending on the lesion characteristics.

scholarly journals Transcriptome-wide Profiling of Cerebral Cavernous Malformations Patients Reveal Important Long noncoding RNA molecular signatures

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Santhilal Subhash ◽  
Norman Kalmbach ◽  
Florian Wegner ◽  
Susanne Petri ◽  
Torsten Glomb ◽  
...  
Keyword(s):  
Noncoding Rna ◽  
Vascular Malformations ◽  
Cerebrovascular Disorders ◽  
Gene Set Enrichment Analysis ◽  
Differentially Expressed ◽  
Low Flow ◽  
Pcr Analysis ◽  
Cerebral Cavernous Malformations ◽  
Cavernous Malformations ◽  
Non Coding Rnas

AbstractCerebral cavernous malformations (CCMs) are low-flow vascular malformations in the brain associated with recurrent hemorrhage and seizures. The current treatment of CCMs relies solely on surgical intervention. Henceforth, alternative non-invasive therapies are urgently needed to help prevent subsequent hemorrhagic episodes. Long non-coding RNAs (lncRNAs) belong to the class of non-coding RNAs and are known to regulate gene transcription and involved in chromatin remodeling via various mechanism. Despite accumulating evidence demonstrating the role of lncRNAs in cerebrovascular disorders, their identification in CCMs pathology remains unknown. The objective of the current study was to identify lncRNAs associated with CCMs pathogenesis using patient cohorts having 10 CCM patients and 4 controls from brain. Executing next generation sequencing, we performed whole transcriptome sequencing (RNA-seq) analysis and identified 1,967 lncRNAs and 4,928 protein coding genes (PCGs) to be differentially expressed in CCMs patients. Among these, we selected top 6 differentially expressed lncRNAs each having significant correlative expression with more than 100 differentially expressed PCGs. The differential expression status of the top lncRNAs, SMIM25 and LBX2-AS1 in CCMs was further confirmed by qRT-PCR analysis. Additionally, gene set enrichment analysis of correlated PCGs revealed critical pathways related to vascular signaling and important biological processes relevant to CCMs pathophysiology. Here, by transcriptome-wide approach we demonstrate that lncRNAs are prevalent in CCMs disease and are likely to play critical roles in regulating important signaling pathways involved in the disease progression. We believe, that detailed future investigations on this set of identified lncRNAs can provide useful insights into the biology and, ultimately, contribute in preventing this debilitating disease.

Regional parenchymal enhancement with mixed cavernous/venous malformations of the brain

1997 ◽  
Vol 86 (1) ◽  
pp. 154-158 ◽  
Author(s):  
Christopher H. Comey ◽  
Douglas Kondziolka ◽  
Howard Yonas
Keyword(s):  
Clinical Symptoms ◽  
Vascular Malformations ◽  
Venous Hypertension ◽  
Venous Malformations ◽  
True Nature ◽  
Cavernous Malformations ◽  
Content Type ◽  
Growth Factor Release ◽  
The Brain ◽  
Parenchymal Enhancement

✓ With improvements in imaging technology, the detection of both cavernous malformations and venous malformations has increased markedly in recent years. Although much has been learned about the association of cavernous and venous malformations, important questions regarding the true nature of such a relationship remain unanswered. It has been proposed that certain venous malformations produce local venous hypertension with resultant microhemorrhage, growth factor release, and creation of cavernous malformations. The authors report on two patients with cerebellopontine venous malformations associated with cavernous malformations. Both patients demonstrated persistent regional parenchymal enhancement associated with the vascular malformations. In addition, both patients had significant clinical symptoms referable to the region of affected brain. This previously undescribed finding may represent an imaging correlate to the complex interaction among venous malformations, venous hypertension, and cavernous malformations.

Stereotactic Radiosurgery of Angiographically Occult Vascular Malformations: Indications and Preliminary Experience

Neurosurgery ◽  
1990 ◽  
Vol 27 (6) ◽  
pp. 892-900 ◽  
Author(s):  
Douglas Kondziolka ◽  
L. Dade Lunsford ◽  
Robert J. Coffey ◽  
David J. Bissonette ◽  
John C. Flickinger
Keyword(s):  
Magnetic Resonance Imaging ◽  
Magnetic Resonance ◽  
Stereotactic Radiosurgery ◽  
Vascular Malformations ◽  
Neurological Deficits ◽  
Resonance Imaging ◽  
University Of Pittsburgh ◽  
History Of ◽  
The Brain

Abstract Stereotactic radiosurgery has been shown to treat successfully angiographically demonstrated arteriovenous malformations of the brain. Angiographic obliteration has represented cure and eliminated the risk of future hemorrhage. The role of radiosurgery in the treatment of angiographically occult vascular malformations (AOVMs) has been less well defined. In the initial 32 months of operation of the 201-source cobalt-60 gamma knife at the University of Pittsburgh, 24 patients meeting strict criteria for high-risk AOVMs were treated. Radiosurgery was used conservatively; each patient had sustained two or more hemorrhages and had a magnetic resonance imaging-defined AOVM located in a region of the brain where microsurgical removal was judged to pose an excessive risk. Venous angiomas were excluded by performance of high-resolution subtraction angiography in each patient. Fifteen malformations were in the medulla, pons, and/or mesencephalon, and 5 were located in the thalamus or basal ganglia. Follow-up ranged from 4 to 24 months. Nineteen patients either improved or remained clinically stable and did not hemorrhage again during the follow-up interval. One patient suffered another hemorrhage 7 months after radiosurgery. Five patients experienced temporary worsening of pre-existing neurological deficits that suggested delayed radiation injury. Magnetic resonance imaging demonstrated signal changes and edema surrounding the radiosurgical target. Dose-volume guidelines for avoiding complications were constructed. Our initial experience indicates that stereotactic radiosurgery can be performed safely in patients with small, well-circumscribed AOVMs located in deep, critical, or relatively inaccessible cerebral locations. Because cerebral angiography is not useful in following patients with AOVMs, long-term magnetic resonance imaging and clinical studies will be necessary to determine whether the natural history of such lesions is changed by radiosurgery.

scholarly journals Cerebral cavernous malformation in a patient with pontine hemorrhage: A case study

2020 ◽  
Vol 10 (3) ◽  
Author(s):  
Myrto Palkopoulou ◽  
Eleni Bakola ◽  
Marina Foliadi ◽  
Petros Stefanidis ◽  
P. Teresa Acquaviva
Keyword(s):  
Magnetic Resonance ◽  
Medical History ◽  
Intracranial Hemorrhage ◽  
De Novo ◽  
Vascular Malformations ◽  
Magnetic Resonance Tomography ◽  
Neurological Deficits ◽  
Cavernous Malformations ◽  
Vascular Walls ◽  
Pontine Hemorrhage

The cerebral cavernous malformations are benign vascular hamartomas, with thin and dilated vascular walls and therefore constantly susceptible to hemorrhage. Clinically, they present with recurrent headaches, acute intracranial hemorrhage and focal neurological deficits. They are considered as angiographically occult vascular malformations and the imaging technique of choice for their diagnosis is magnetic resonance tomography. We present the case of a female patient with acute-onset symptomatology, congruent with a lesion in the basal pons. Her medical history included an intracranial hemorrhage due to a cavernoma, which was surgically removed. The magnetic resonance imaging of the brain revealed two new cavernomas, which were not identified in the imaging conducted in the past. In literature, the cases of de novo appearance of cavernomas are considered highly rare, especially in patients with no consistent family history or medical history of radiation therapy. Resultantly, they should be considered as dynamic lesions, regarding their number, size and behavior.

scholarly journals Genetic Genealogy Uncovers a Founder Deletion Mutation in the Cerebral Cavernous Malformations 2 Gene

2021 ◽  
Author(s):  
Carol J Gallione ◽  
Matthew R Detter ◽  
Henrietta M Christmas ◽  
Cornelia Lee ◽  
Douglas A Marchuk
Keyword(s):  
Vascular Malformations ◽  
Cerebral Cavernous Malformations ◽  
Autosomal Dominant Trait ◽  
Cavernous Malformations ◽  
North American Continent ◽  
The North ◽  
Genealogical Data ◽  
The Brain ◽  
Recombination Junction ◽  
Pair Level

Abstract Cerebral cavernous malformations (CCM) are vascular malformations consisting of collections of enlarged capillaries occurring in the brain or spinal cord. These vascular malformations can occur sporadically or susceptibility to develop these can be inherited as an autosomal dominant trait due to mutation in one of three genes. Over a decade ago, we described a 77.6 Kb germline deletion spanning exons 2-10 in the CCM2 gene found in multiple affected individuals from seemingly unrelated families. Segregation analysis using linked, microsatellite markers indicated that this deletion may have arisen at least twice independently. In the ensuing decades, many more CCM patients have been identified with this deletion. In this present study we examined 27 reportedly unrelated affected individuals with this deletion. To investigate the origin of the deletion at base pair level resolution, we sequenced approximately 10 Kb upstream and downstream from the recombination junction on the deleted allele. All patients showed the identical SNP haplotype across this combined 20 Kb interval. In parallel, genealogical records have traced 11 of these individuals to five separate pedigrees dating as far back as the 1600-1700’s. These haplotype and genealogical data suggest that these families and the remaining “unrelated” samples converge on a common ancestor due to a founder mutation occurring centuries ago on the North American continent. We also note that another gene, NACAD, is included in this deletion. Although patient self-reporting does not indicate an apparent phenotypic consequence for heterozygous deletion of NACAD, further investigation is warranted for these patients.

scholarly journals Neurocysticercosis, familial cerebral cavernomas and intracranial calcifications: differential diagnosis for adequate management

2016 ◽  
Vol 74 (6) ◽  
pp. 495-500 ◽  
Author(s):  
Emerson Leandro Gasparetto ◽  
Soniza Alves-Leon ◽  
Flavio Sampaio Domingues ◽  
João Thiago Frossard ◽  
Selva Paraguassu Lopes ◽  
...  
Keyword(s):  
Differential Diagnosis ◽  
Health Problem ◽  
Vascular Malformations ◽  
Chronic Phase ◽  
Public Health Problem ◽  
Cranial Computed Tomography ◽  
Cavernous Malformations ◽  
Familial Form ◽  
Adequate Management ◽  
The Brain

ABSTRACT Neurocysticercosis (NCC) is an endemic disease and important public health problem in some areas of the World and epilepsy is the most common neurological manifestation. Multiple intracranial lesions, commonly calcified, are seen on cranial computed tomography (CT) in the chronic phase of the disease and considered one of the diagnostic criteria of the diagnosis. Magnetic resonance imaging (MRI) is the test that better depicts the different stages of the intracranial cysts but does not show clearly calcified lesions. Cerebral cavernous malformations (CCM), also known as cerebral cavernomas, are frequent vascular malformations of the brain, better demonstrated by MRI and have also epilepsy as the main form of clinical presentation. When occurring in the familial form, cerebral cavernomas typically present with multiple lesions throughout the brain and, very often, with foci of calcifications in the lesions when submitted to the CT imaging. In the countries, and geographic areas, where NCC is established as an endemic health problem and neuroimaging screening is done by CT scan, it will be important to consider the differential diagnosis between the two diseases due to the differences in adequate management.

Effective surgical treatment of cerebral cavernous malformations: a multicenter study of 79 pediatric patients

2011 ◽  
Vol 8 (5) ◽  
pp. 522-525 ◽  
Author(s):  
Michael Hugelshofer ◽  
Nicola Acciarri ◽  
Ulrich Sure ◽  
Dimitrios Georgiadis ◽  
Ralf W. Baumgartner ◽  
...  
Keyword(s):  
Pediatric Patients ◽  
Refractory Epilepsy ◽  
Epileptic Seizures ◽  
Neurological Deficits ◽  
Vascular Lesions ◽  
Cerebral Cavernous Malformations ◽  
Cavernous Malformations ◽  
Persistent Symptoms ◽  
The Mean ◽  
The Brain

Object Cerebral cavernous malformations (CCMs) are common vascular lesions in the brain, affecting approximately 0.5% of the population and representing 10%–20% of all cerebral vascular lesions. One-quarter of all CCMs affect pediatric patients, and CCMs are reported as one of the main causes of brain hemorrhage in this age group. Symptoms include epileptic seizures, headache, and focal neurological deficits. Patients with symptomatic CCMs can be treated either conservatively or with resection if lesions cause medically refractory epilepsy or other persistent symptoms. Methods The authors retrospectively analyzed 79 pediatric patients (41 boys and 38 girls) from 3 different centers, who were surgically treated for their symptomatic CCMs between 1974 and 2004. The mean age of the children at first manifestation was 9.7 years, and the mean age at operation was 11.3 years. The main goal was to compare the clinical outcomes with respect to the location of the lesion of children who preoperatively suffered from epileptic seizures. Results Of these patients, 77.3% were seizure free (Engel Class I) after the resection of the CCM. Significant differences in the outcome between children who harbored CCMs at different locations were not found. Conclusions Resection seems to be the favorable treatment of symptomatic CCMs not only in adults but also in children.

scholarly journals Genetic testing for cerebral cavernous malformations

2018 ◽  
Vol 2 (s1) ◽  
pp. 83-85
Author(s):  
Yeltay Rakhmanov ◽  
Paolo Enrico Maltese ◽  
Carla Marinelli ◽  
Leonardo D’Agruma ◽  
Tommaso Beccari ◽  
...  
Keyword(s):  
Risk Assessment ◽  
Autosomal Dominant ◽  
Vascular Malformations ◽  
Cerebral Cavernous Malformations ◽  
Dominant Inheritance ◽  
Focal Neurological Deficit ◽  
Cavernous Malformations ◽  
Gene Test ◽  
Brain And Spinal Cord ◽  
The Brain

Abstract Cavernous cerebral malformations (CCM) are vascular malformations of the brain and spinal cord. CCM affect up to 0.5% of the general population, predisposing to headaches, seizures, cerebral hemorrhage and focal neurological deficit. CCM may be familial or sporadic. Familial forms have autosomal dominant inheritance. This Utility Gene Test was prepared on the basis of an analysis of the literature and existing diagnostic protocols. It is useful for confirming diagnosis, as well as for differential diagnosis, couple risk assessment and access to clinical trials.

Management of incidental cavernous malformations: a review

2011 ◽  
Vol 31 (6) ◽  
pp. E5 ◽  
Author(s):  
Richard T. Dalyai ◽  
George Ghobrial ◽  
Issam Awad ◽  
Stavropoula Tjoumakaris ◽  
L. Fernando Gonzalez ◽  
...  
Keyword(s):  
Mr Imaging ◽  
Vascular Malformations ◽  
Imaging Techniques ◽  
Therapeutic Interventions ◽  
Neurological Deficits ◽  
Optimal Management ◽  
Review Of The Literature ◽  
Cavernous Malformations ◽  
Concise Review ◽  
Symptomatic Intracranial Hemorrhage

Cavernous malformations (CMs) are angiographically occult vascular malformations that are frequently found incidentally on MR imaging. Despite this benign presentation, these lesions could cause symptomatic intracranial hemorrhage, seizures, and focal neurological deficits. Cavernomas can be managed conservatively with neuroimaging studies, surgically with lesion removal, or with radiosurgery. Considering recent studies examining the CM's natural history, imaging techniques, and possible therapeutic interventions, the authors provide a concise review of the literature and discuss the optimal management of incidental CMs.

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