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 Developmental timing of CCM2 loss influences cerebral cavernous malformations in mice

2011 ◽  
Vol 208 (9) ◽  
pp. 1835-1847 ◽  
Author(s):  
Gwénola Boulday ◽  
Noemi Rudini ◽  
Luigi Maddaluno ◽  
Anne Blécon ◽  
Minh Arnould ◽  
...  
Keyword(s):  
Autosomal Dominant ◽  
Vascular Malformations ◽  
Vascular Lesions ◽  
Developmental Timing ◽  
Cerebral Cavernous Malformations ◽  
Loss Of Function ◽  
Cavernous Malformations ◽  
The Central Nervous System ◽  
Dominant Condition

Cerebral cavernous malformations (CCM) are vascular malformations of the central nervous system (CNS) that lead to cerebral hemorrhages. Familial CCM occurs as an autosomal dominant condition caused by loss-of-function mutations in one of the three CCM genes. Constitutive or tissue-specific ablation of any of the Ccm genes in mice previously established the crucial role of Ccm gene expression in endothelial cells for proper angiogenesis. However, embryonic lethality precluded the development of relevant CCM mouse models. Here, we show that endothelial-specific Ccm2 deletion at postnatal day 1 (P1) in mice results in vascular lesions mimicking human CCM lesions. Consistent with CCM1/3 involvement in the same human disease, deletion of Ccm1/3 at P1 in mice results in similar CCM lesions. The lesions are located in the cerebellum and the retina, two organs undergoing intense postnatal angiogenesis. Despite a pan-endothelial Ccm2 deletion, CCM lesions are restricted to the venous bed. Notably, the consequences of Ccm2 loss depend on the developmental timing of Ccm2 ablation. This work provides a highly penetrant and relevant CCM mouse model.

Novel CCM2 missense variants abrogating the CCM1–CCM2 interaction cause cerebral cavernous malformations

2020 ◽  
Vol 57 (6) ◽  
pp. 400-404
Author(s):  
Françoise Bergametti ◽  
Geraldine Viot ◽  
Christophe Verny ◽  
Marie Pierre Brechard ◽  
Christian Denier ◽  
...  
Keyword(s):  
Central Nervous System ◽  
Vascular Malformations ◽  
Cerebral Cavernous Malformations ◽  
Complex Stability ◽  
Loss Of Function ◽  
Molecular Screening ◽  
Cavernous Malformations ◽  
Missense Variants ◽  
The Central Nervous System ◽  
Ptb Domain

BackgroundCerebral cavernous malformations (CCMs) are vascular malformations mostly located within the central nervous system. Most deleterious variants are loss of function mutations in one of the three CCM genes. These genes code for proteins that form a ternary cytosolic complex with CCM2 as a hub. Very few CCM2 missense variants have been shown to be deleterious by modifying the ternary CCM complex stability.ObjectivesTo investigate the causality of novel missense CCM2 variants detected in patients with CCM.MethodsThe three CCM genes were screened in 984 patients referred for CCM molecular screening. Interaction between CCM1 and CCM2 proteins was tested using co-immunoprecipitation experiments for the CCM2 missense variants located in the phosphotyrosine binding (PTB) domain.Results11 distinct CCM2 rare missense variants were found. Six variants predicted to be damaging were located in the PTB domain, four of them were novel. When co-transfected with CCM1 in HEK293T cells, a loss of interaction between CCM1 and CCM2 was observed for all six variants.ConclusionWe showed, using co-immunoprecipitation experiments, that CCM2 missense variants located in the PTB domain were actually damaging by preventing the normal interaction between CCM1 and CCM2. These data are important for diagnosis and genetic counselling, which are challenging in patients harbouring such variants.

Cerebral Cavernous Malformations: Patient-Reported Outcome Validates Conservative Management

2017 ◽  
Vol 44 (5-6) ◽  
pp. 313-319 ◽  
Author(s):  
Vitor Chehuen Bicalho ◽  
Anke Bergmann ◽  
Flávio Domingues ◽  
João Thiago Frossard ◽  
Jorge Paes Barreto Marcondes de Souza
Keyword(s):  
Vascular Malformations ◽  
Patient Reported Outcome ◽  
Neurological Deficits ◽  
Cerebral Cavernous Malformations ◽  
Cavernous Malformations ◽  
Familial Form ◽  
Sf 36 ◽  
Patient Reported

Background: Cerebral cavernous malformations (CCM) are clusters of dilated sinusoidal channels lined by a single layer of endothelium. In contradistinction to arteriovenous malformations, these lesions do not have smooth muscle or elastin in their lining and they are angiographically occult, and the MRI is the most sensitive test for CCM detection. CCM are one of the most prevalent vascular malformations of the central nervous system, affecting about 0.4-0.6% of the general population. The main complication of this malformation is the risk of bleeding, which may cause neurological deficits that affect the quality of life (QoL) in patients. When symtomatic, they may be surgically treated for relieving the mass effect and seizures refractory to drug uses, hemorrhage and drug-refractory epilepsy. Patient-reported outcome (PRO) may be a strategy that can be used to evaluate QoL of CCM population and was used in a sample of non-operated patients. Methods: An observational, cross-sectional analysis to evaluate the PRO using the SF-36 and EuroQol 5 dimensions (EQ-5D) questionnaires of QoL added to functional metrics using the Karnofsky Performance Status (KPS) in 49 patients not submitted to intervention and with long-term follow-up. Results: During the 364 person-years of follow-up, there was an average of individual follow-up of 7.42 years. The mean age was 46.8 years (18-84) - 57% of them were female, 71% had superficial lesions, and 65% had the familial form. Comparisons of SF-36 dimensions with KPS graded <100 had a worse score only in terms of the pain (p = 0.04), vitality (p = 0.001), and general state of health (p = 0.03) domains. The domain mental health was worse in patients without surgical indication (p = 0.032). The functional capacity domain had the highest overall grading in the group. The EQ-5D dimensions of mobility (p = 0.03) and pain/discomfort (p = 0.001) were the ones with lower score compared to KPS <100. Conclusion: The study is the first to evaluate, with validated tools, the PRO of non-operated CCM patients and has demonstrated in a selected group of patients that it was possible to achieve long-term clinical stability, thereby maintaining QoL and functional neurological outcome.

scholarly journals Predictors of mortality in patients with hereditary hemorrhagic telangiectasia

2021 ◽  
Vol 16 (1) ◽  
Author(s):  
K. P. Thompson ◽  
◽  
J. Nelson ◽  
H. Kim ◽  
L. Pawlikowska ◽  
...  
Keyword(s):  
Hereditary Hemorrhagic Telangiectasia ◽  
Cox Regression ◽  
Clinical Symptoms ◽  
Vascular Malformations ◽  
Smoking Status ◽  
Treatment Options ◽  
Gi Bleeding ◽  
Cox Regression Analysis ◽  
Predictors Of Mortality

Abstract Background Retrospective questionnaire and healthcare administrative data suggest reduced life expectancy in untreated hereditary hemorrhagic telangiectasia (HHT). Prospective data suggests similar mortality, to the general population, in Denmark’s centre-treated HHT patients. However, clinical phenotypes vary widely in HHT, likely affecting mortality. We aimed to measure predictors of mortality among centre-treated HHT patients. HHT patients were recruited at 14 HHT centres of the Brain Vascular Malformation Consortium (BVMC) since 2010 and followed annually. Vital status, organ vascular malformations (VMs) and clinical symptoms data were collected at baseline and during follow-up (N = 1286). We tested whether organ VMs, HHT symptoms and HHT genes were associated with increased mortality using Cox regression analysis, adjusting for patient age, sex, and smoking status. Results 59 deaths occurred over average follow-up time of 3.4 years (max 8.6 years). A history of anemia was associated with increased mortality (HR = 2.93, 95% CI 1.37–6.26, p = 0.006), as were gastro-intestinal (GI) bleeding (HR = 2.63, 95% CI 1.46–4.74, p = 0.001), and symptomatic liver VMs (HR = 2.10, 95% CI 1.15–3.84, p = 0.015). Brain VMs and pulmonary arteriovenous malformations (AVMs) were not associated with mortality (p > 0.05). Patients with SMAD4 mutation had significantly higher mortality (HR = 18.36, 95% CI 5.60–60.20, p < 0.001) compared to patients with ACVRL1 or ENG mutation, but this estimate is imprecise given the rarity of SMAD4 patients (n = 33, 4 deaths). Conclusions Chronic GI bleeding, anemia and symptomatic liver VMs are associated with increased mortality in HHT patients, independent of age, and in keeping with the limited treatment options for these aspects of HHT. Conversely, mortality does not appear to be associated with pulmonary AVMs or brain VMs, for which patients are routinely screened and treated preventatively at HHT Centres. This demonstrates the need for development of new therapies to treat chronic anemia, GI bleeding, and symptomatic liver VMs in order to reduce mortality among HHT patients.

Abstract 159: Exceptional Aggressiveness of CCM3 Phenotype

Stroke ◽  
2014 ◽  
Vol 45 (suppl_1) ◽  
Author(s):  
Tania J Rebeiz ◽  
Abdul Ghani Mikati ◽  
Darlene Simkhin ◽  
Cornelia Lee ◽  
Amy Akers ◽  
...  
Keyword(s):  
Spontaneous Mutation ◽  
Mutation Screening ◽  
High Sensitivity ◽  
Skin Lesions ◽  
Cerebral Cavernous Malformations ◽  
Cognitive Disability ◽  
Cavernous Malformations ◽  
Patient Advocacy Group ◽  
Sporadic Cases

Introduction: Familial forms of cerebral cavernous malformations (CCM) account for about 1/3 of cases, involving autosomal dominant inheritance at 1 of 3 gene loci. Few studies have examined any special features of the rarest cases with CCM3 (PDCD10 ) mutation at q3, constituting <15 % of probands genotyped by sequential mutation screening, and <2% of CCM cases at large. Hypothesis: We hypothesize that CCM3 cases have unique phenotypic features not recognized in the more common CCM1 and 2 families, or in sporadic cases. Methods: Twelve probands including 17 subjects with confirmed CCM3 mutations were prospectively enrolled through systematic facilitated referral by the patient advocacy group Angioma Alliance. Clinical features were catalogued, including high sensitivity susceptibility weighted imaging (SWI). Rates of overt hemorrhage were determined based on adjudicated criteria. Comparisons were made to systematic literature review of natural history data on non-CCM3 cases. Results: The first overt hemorrhage occurred most often in the 1st decade of life (mean age 5.8). Nine of 17 subjects (52%) suffered 30 overt hemorrhages, with an estimated incidence of 6.7 % /patient/year based on exposure risk since birth, and 17% /patient/year based on risk since first symptom onset. Lesion burden on SWI was exceptionally high, >100 lesions in 28%, and > 20 lesions in 72% of cases, respectively. Adjusted bleed rate was <0.5% /lesion/year. New SWI lesions formed at a rate of 2.7/patient/year in prospective follow-up, and 1.8/patient/year based on years since birth. Scoliosis was found in 47% (an association not recognized previously), skin lesions in 29.4%, and brain tumors in 29.4% of cases, respectively. Cognitive disability affected 47% of cases, mostly in association with high lesion burden. Six of 15 cases with parental screening (40%) represented a spontaneous mutation. Conclusion: CCM3 is exceptionally aggressive compared to other familial and sporadic CCM. High risks of bleeding and cognitive disability mostly reflect severe lesion burden early in life, rather than a higher risk per lesion. These results will inform the design of clinical trials, urgently needed to address this unique CCM cohort.

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.

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 A bent needle tip during irrigation for enchondroma of the distal phalanx: a new curettage tool

2019 ◽  
Vol 48 (3) ◽  
pp. 030006051989236
Author(s):  
Eiji Osaka ◽  
Toshio Kojima ◽  
Yukihiro Yoshida ◽  
Hiroshi Uei
Keyword(s):  
Calcium Phosphate ◽  
Clinical Symptoms ◽  
Tumor Location ◽  
Distal Phalanx ◽  
Small Hole ◽  
Extension Tube ◽  
Mean Size ◽  
Small Bones ◽  
Radiological Examinations

Background We employed a novel curettage tool, a bent needle tip, during irrigation for enchondroma of the distal phalanx. This study aimed to evaluate our new curettage tool for treating enchondroma of the distal phalanx. Methods Seven distal phalanx enchondromas were pathologically diagnosed at our institute. We evaluated age, gender, tumor location, affected side, clinical symptoms, Takigawa classification, size, recurrence, complications, residual pain, Tordai score, and follow-up period. We bent an 18G needle tip connected to an extension tube and syringe. The bent needle was inserted through the small hole, and the cavity for bone grafting was adequately filled with injectable calcium phosphate cement through the small hole. Results There were five centric-type and two giant-type tumors, with a mean size of 52.7%. All patients had clinical symptoms at the initial presentation. All patients showed complete bone healing within 3 months on post-radiological examinations and were Grade 1 according to the Tordai score. Conclusions This tool is extremely simple, and both the incision and the cortical window can be small. We recommend a bent needle tip, easily devised in any hospital, as a curettage tool for treating enchondroma in small bones, especially of the distal phalanx.

scholarly journals Supratentorial cerebral cavernous malformations: clinical, surgical, and genetic involvement

2006 ◽  
Vol 21 (1) ◽  
pp. 1-7 ◽  
Author(s):  
Vincenzo Antonio D'Angelo ◽  
Costanzo De Bonis ◽  
Rosina Amoroso ◽  
Alessandro Calì ◽  
Leonardo D'Agruma ◽  
...  
Keyword(s):  
Mutational Analysis ◽  
Family Members ◽  
Neurological Deficits ◽  
Cerebral Cavernous Malformations ◽  
Cavernous Malformations ◽  
Psychological Burden ◽  
Management Algorithm ◽  
Screening Protocol

Object Although there is general agreement on the methods of treatment for symptomatic supratentorial cerebral cavernous malformations (CMs) located in noneloquent areas, some controversy exists regarding the management of cerebral CMs that are asymptomatic and/or located in eloquent or deep areas. Moreover, recent advances in genetic findings could influence both standard clinical management and the follow-up strategy in affected individuals. Thus, the objective of this study was to develop, based on the authors' experience and a literature review, a management algorithm to deal with supratentorial cerebral CMs. Methods The authors retrospectively reviewed the clinical data related to 118 patients who underwent surgery for symptomatic supratentorial cerebral CMs at their institution. Twenty-eight of 118 patients harbored multiple lesions, and nine of these 28 patients had a clinically positive familial history. Genetic investigations were performed in 89 patients (75%). Conclusions Surgery for supratentorial cerebral CMs in noneloquent locations is safe and curative. In cerebral CMs located in deep and eloquent areas and with symptoms including progressive neurological deficits, evidence of hemorrhage, and uncontrolled seizures, surgical treatment according to an integrated plan based on frameless stereotactic guidance and functional magnetic resonance imaging is recommended and results in acceptably low morbidity. The data support the need for long-term imaging follow up in all patients, careful preoperative vascular studies to detect associated venous anomalies, and the importance of genetic mutational analysis. The DNA screening protocol will change the care of family members of patients with familial forms of cerebral CMs, because affected asymptomatic family members may benefit by early detection of lesions. At the same time, the exclusion of family members who are not carriers of the mutation as members of the population at risk reduces the economic and psychological burden of clinical and instrumental monitoring.

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.

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