Aeromedical Implications of Cerebral Cavernomas

2021 ◽  
Vol 92 (2) ◽  
pp. 120-123
Author(s):  
Tania Jagathesan ◽  
Michael OBrien
Keyword(s):  
Clinical Presentation ◽  
Clinical Symptoms ◽  
Civil Aviation ◽  
Complication Rates ◽  
Cerebral Cavernous Malformations ◽  
Cavernous Malformations ◽  
Medical Certification ◽  
The Uk ◽  
Age Range ◽  
The Brain

BACKGROUND: Cavernomas, cavernous angiomas, or cerebral cavernous malformations are clusters of endothelium-lined blood vessels usually found in the brain. With the increasing use of radiological imaging, these are being detected incidentally in asymptomatic aircrew. The UK Civil Aviation Authority (CAA) experience of cavernomas is described and the aeromedical concerns, that is, the risk of epilepsy, hemorrhage, and the development of a neurological deficit, are considered.METHODS: A search of the CAA database between 1990 and 2020 was performed for the term cavernoma. The gender, age at diagnosis, class of certification held, clinical presentation, location, and size of the lesion were noted. A PubMed literature review for papers with complications of cavernoma was performed.RESULTS: Six cases of cavernoma have been declared to the CAA: five professional pilots and one private pilot. Five were men and one was a woman. The age range was between 38 and 60 yr, with a mean of 48 yr. Two cases presented with clinical symptoms and four were asymptomatic. Complication rates for seizure and hemorrhage were extracted from the published literature together with the significance of other factors such as cavernoma size, family history, multiplicity, and the development of new lesions.DISCUSSION: A policy for the medical certification of aircrew with cavernomas that have presented with clinical symptoms and those that are detected incidentally is proposed.Jagathesan T, OBrien M. Aeromedical implications of cerebral cavernomas. Aerosp Med Hum Perform. 2021; 92(2):120123.

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 Mural Cell-Specific Deletion of Cerebral Cavernous Malformation 3 in the Brain Induces Cerebral Cavernous Malformations

2020 ◽  
Vol 40 (9) ◽  
pp. 2171-2186
Author(s):  
Kang Wang ◽  
Haifeng Zhang ◽  
Yun He ◽  
Quan Jiang ◽  
Yoshiaki Tanaka ◽  
...  
Keyword(s):  
Endothelial Cell ◽  
Adhesion Formation ◽  
Single Layer ◽  
Cerebral Cavernous Malformations ◽  
Mural Cell ◽  
Cavernous Malformations ◽  
Mural Cells ◽  
Brain Pericytes ◽  
The Brain ◽  
Specific Deletion

Objective: Cerebral cavernous malformations (CCM), consisting of dilated capillary channels formed by a single layer of endothelial cells lacking surrounding mural cells. It is unclear why CCM lesions are primarily confined to brain vasculature, although the 3 CCM-associated genes ( CCM1 , CCM2 , and CCM3 ) are ubiquitously expressed in all tissues. We aimed to determine the role of CCM gene in brain mural cell in CCM pathogenesis. Approach and Results: SM22α -Cre was used to drive a specific deletion of Ccm3 in mural cells, including pericytes and smooth muscle cells (Ccm3smKO). Ccm3smKO mice developed CCM lesions in the brain with onset at neonatal stages. One-third of Ccm3smKO mice survived upto 6 weeks of age, exhibiting seizures, and severe brain hemorrhage. The early CCM lesions in Ccm3smKO neonates were loosely wrapped by mural cells, and adult Ccm3smKO mice had clustered and enlarged capillary channels (caverns) formed by a single layer of endothelium lacking mural cell coverage. Importantly, CCM lesions throughout the entire brain in Ccm3smKO mice, which more accurately mimicked human disease than the current endothelial cell-specific CCM3 deletion models. Mechanistically, CCM3 loss in brain pericytes dramatically increased paxillin stability and focal adhesion formation, enhancing ITG-β1 (integrin β1) activity and extracellular matrix adhesion but reducing cell migration and endothelial cell-pericyte associations. Moreover, CCM3-wild type, but not a paxillin-binding defective mutant, rescued the phenotypes in CCM3-deficient pericytes. Conclusions: Our data demonstrate for the first time that deletion of a CCM gene in the brain mural cell induces CCM pathogenesis.

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.

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 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.

Cerebral cavernous malformations: epidemiological, clinical and diagnostic imaging aspects

2018 ◽  
Vol 8 (2) ◽  
pp. 8-17
Author(s):  
I. Czekalska ◽  
Z. Tyrakowska-Dadełło ◽  
P. Werel ◽  
E. Tarasów ◽  
E. Grodzka
Keyword(s):  
Clinical Symptoms ◽  
Vascular Malformations ◽  
Epileptic Seizures ◽  
Cerebral Cavernous Malformations ◽  
Cavernous Malformations ◽  
Large Size ◽  
Wide Range ◽  
Mean Size ◽  
The Central Nervous System

<b>Introduction:</b> Cerebral cavernous malformations (CCMs) are one of the most common vascular malformations of the central nervous system. Symptoms of CCMs are not typical; the disease can be asymptomatic or be manifested by a wide range of neurological symptoms. <b>Purpose:</b> To evaluate chosen epidemiologic and clinical issues as well as advanced imaging diagnostics of CCMs in computed tomography and magnetic resonance imaging. <b>Materials and methods:</b> The study was based on retrospective analysis of CT and MRI examinations from the 5 years period. The analysis covered 61 persons, 29 males, and 32 females. The CCMs were diagnosed based on MRI examination in 43 patients and CT in 13 patients. <b>Results:</b> The rate of CCMs occurrence in own material was 0.2%. Single lesions were present in 90.2%, while multiple in 9.8% of cases. Supratentorial CCMs were observed in 77% of cases whereas subtentorial in 23%. Mean size of CCMs in the supra- and subtentorial area equaled 10.6±6.3 and 15.1±5.8 mm, respectively (p<0.05). Clinical symptoms occurred in 65.8% of patients, most frequently in patients with CCMs above 5 mm or with subtentorial lesions. All CCMs were hyperdense in CT images, with calcifications in 13.1%. In MRI, malformations showed diverse intensity of the central part with peripheral low-intensity rim of hemosiderine deposits in T2-weighted images. <b>Conclusions:</b> The clinical symptoms occur in most cases of CCMs. These patients require periodic follow-up MRI examinations, specifically those with haemorrhagic incidents or epileptic seizures, with large size or subtentorial CCMs.

scholarly journals CCM2 deficient endothelial cells undergo a mechano-dependent reprogramming into senescence associated secretory phenotype used to recruit endothelial and immune cells

2021 ◽  
Author(s):  
Daphné Raphaëlle Vannier ◽  
Apeksha Shapeti ◽  
Florent Chuffart ◽  
Emmanuelle Planus ◽  
Sandra Manet ◽  
...  
Keyword(s):  
Extracellular Matrix ◽  
Endothelial Cells ◽  
Cerebrovascular Disease ◽  
Immune Cells ◽  
Cerebral Cavernous Malformations ◽  
Wild Type ◽  
Cellular Mechanics ◽  
Cavernous Malformations ◽  
Secretory Phenotype ◽  
The Brain

AbstractCerebral Cavernous Malformations (CCM) is a cerebrovascular disease in which stacks of dilated haemorrhagic capillaries form focally in the brain. Whether and how defective mechanotransduction, cellular mosaicism and inflammation interplay to sustain the progression of CCM diseases is unknown. Here, we reveal that CCM1- and CCM2-silenced endothelial cells enter into senescence associated with secretory phenotype (SASP) that they use to invade the extracellular matrix and attract surrounding wild-type endothelial and immune cells. Further, we demonstrate that this SASP is driven by the mechanical and molecular disorders provoked by ROCKs dysfunctions. By this, we identify CCM1/2 and ROCKs as parts of a scaffold controlling senescence, bringing new insights into the emerging field of the control of aging by cellular mechanics. This discovery reconciles the dysregulated traits of CCM1/2-deficient endothelial cells into a unique mechano-dependent endothelial fate that links perturbed mechanics to microenvironment remodelling and long-range activation of endothelial and immune cells.

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.

scholarly journals Developmental Venous Anomalies are a Genetic Primer for Cerebral Cavernous Malformations

2021 ◽  
Author(s):  
Daniel A. Snellings ◽  
Romuald Girard ◽  
Rhonda Lightle ◽  
Abhinav Srinath ◽  
Sharbel Romanos ◽  
...  
Keyword(s):  
Somatic Mutations ◽  
Cerebral Cavernous Malformations ◽  
Cavernous Malformations ◽  
Clonal Population ◽  
Signaling Complex ◽  
Venous Anomalies ◽  
Brain Vasculature ◽  
Developmental Venous Anomalies ◽  
Single Nucleus ◽  
The Brain

AbstractCerebral cavernous malformations (CCM) are a neurovascular anomaly that may occur sporadically in otherwise healthy individuals, or be inherited by autosomal dominant mutations in the genes that encode the proteins of the CCM signaling complex (KRIT1, CCM2, or PDCD10)1–4. CCMs have long been known to follow a genetic two-hit model where lesion formation is initiated by somatic mutations resulting in biallelic loss of a CCM complex gene5–8. Recent studies have shown that somatic mutations in MAP3K3 and PIK3CA also contribute to CCM pathogenesis9–11; however, it remains unclear how these mutations contribute to sporadic versus familial cases. Here we show that somatic mutations in MAP3K3 are mutually exclusive with mutations in CCM complex genes and that mutations in MAP3K3 contribute to sporadic, but not familial CCM. Using single-nucleus DNA sequencing, we show that co-occurring MAP3K3 and PIK3CA mutations are present within the same clonal population of cells. Furthermore, we identify PIK3CA mutations in CCM-associated developmental venous anomalies (DVA). It has long been known that sporadic CCM often develop in the vicinity of a DVA. However, the underlying cause of this association is unknown12–14. In this first report of the molecular pathology of CCM-associated DVA, we find that the identical PIKC3A mutation is found in both the DVA and its associated CCM, but that an activating MAP3K3 mutation appears only in the CCM. These results support a mechanism where DVA develop as the result of a PIK3CA mutation, creating a region of the brain vasculature that functions as a genetic primer for CCM development following acquisition of an additional somatic mutation.

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