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 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.

CCM1mutation screen of sporadic cases with cerebral cavernous malformations

Neurology ◽  
2004 ◽  
Vol 62 (7) ◽  
pp. 1213-1215 ◽  
Author(s):  
D. J. Verlaan ◽  
S. B. Laurent ◽  
U. Sure ◽  
H. Bertalanffy ◽  
E. Andermann ◽  
...  
Keyword(s):  
Cerebral Cavernous Malformations ◽  
Cavernous Malformations ◽  
Sporadic Cases

Is Active Follow-Up by Serial Imaging Justified in Patients with Multiple Cerebral Cavernous Malformations?

2018 ◽  
Author(s):  
J. Velz ◽  
M. Stienen ◽  
M. Neidert ◽  
Y. Yang ◽  
L. Regli ◽  
...  
Keyword(s):  
Cerebral Cavernous Malformations ◽  
Cavernous Malformations ◽  
Serial Imaging

Natural Course of Cerebral Cavernous Malformations in Children: A Five-Year Follow-Up Study

Stroke ◽  
2021 ◽  
Author(s):  
Alejandro N. Santos ◽  
Laurèl Rauschenbach ◽  
Dino Saban ◽  
Bixia Chen ◽  
Annika Herten ◽  
...  
Keyword(s):  
Logistic Regression ◽  
Brain Stem ◽  
Odds Ratio ◽  
Pediatric Patients ◽  
Cox Regression ◽  
Cerebral Cavernous Malformations ◽  
Multivariate Logistic Regression ◽  
Cavernous Malformations ◽  
History Of

Background and Purpose: The purpose of this study was to investigate the natural course of cerebral cavernous malformations (CCM) in the pediatric population, with special emphasis on the risk of first and recurrent bleeding over a 5-year period. Methods: Our institutional database was screened for patients with CCM treated between 2003 and 2020. Patients ≤18 years of age with complete magnetic resonance imaging data set, clinical baseline characteristics, and ≥1 follow-up examination were included. Surgically treated individuals were censored after CCM removal. We assessed the impact of various parameters on first or recurrent intracerebral hemorrhage (ICH) at diagnosis using univariate and multivariate logistic regression adjusted for age and sex. Kaplan-Meier and Cox regression analyses were performed to determine the cumulative 5-year risk for (re)hemorrhage. Results: One hundred twenty-nine pediatric patients with CCM were analyzed. Univariate logistic regression identified brain stem CCM (odds ratio, 3.15 [95% CI, 1.15−8.63], P =0.026) and familial history of CCM (odds ratio, 2.47 [95% CI, 1.04−5.86], P= 0.041) as statistically significant predictors of ICH at diagnosis. Multivariate logistic regression confirmed this correlation (odds ratio, 3.62 [95% CI, 1.18−8.99], P= 0.022 and odds ratio, 2.53 [95% CI, 1.07−5.98], P =0.035, respectively). Cox regression analysis identified ICH as mode of presentation (hazard ratio, 14.01 [95% CI, 1.80−110.39], P= 0.012) as an independent predictor for rehemorrhage during the 5-year follow-up. The cumulative 5-year risk of (re)bleeding was 15.9% (95% CI, 10.2%−23.6%) for the entire cohort, 30.2% (20.2%−42.3%) for pediatric patients with ICH at diagnosis, and 29.5% (95% CI, 13.9%−51.1%) for children with brain stem CCM. Conclusions: Pediatric patients with brain stem CCM and familial history of CCM have a higher risk of ICH as mode of presentation. During untreated 5-year follow-up, they revealed a similar risk of (re)hemorrhage compared to adult patients. The probability of (re)bleeding increases over time, especially in cases with ICH at presentation or brain stem localization.

scholarly journals Antithrombotic medication and bleeding risk in patients with cerebral cavernous malformations: a cohort study

2019 ◽  
Vol 130 (6) ◽  
pp. 1922-1930
Author(s):  
David Bervini ◽  
Christian Jaeggi ◽  
Pasquale Mordasini ◽  
Philippe Schucht ◽  
Andreas Raabe
Keyword(s):  
Bleeding Risk ◽  
Cerebral Cavernous Malformations ◽  
Cavernous Malformations ◽  
Vascular Abnormalities ◽  
Increased Risk ◽  
Potential Risk Factors ◽  
Hemorrhagic Risk ◽  
Risk Of Hemorrhage ◽  
Antithrombotic Medication

OBJECTIVECerebral cavernous malformations (CCMs) are frequently diagnosed vascular abnormalities. The hemorrhagic risk associated with the use of long-term antithrombotic medication (ATM) in patients with CCMs is a matter of controversy. The aim of this study was to determine the hemorrhagic risk associated with ATM use in patients diagnosed with one or more CCMs.METHODSDemographic, clinical, treatment, and ATM-related information on patients diagnosed with one or more CCMs at a single institution over more than 34 years was retrospectively recorded. Univariate and multivariate descriptive and survival analyses were used to assess potential risk factors associated with CCM-related hemorrhage at presentation and during follow-up (first or subsequent hemorrhage).RESULTSA total of 408 patients were included in the analysis and 492 CCMs were followed up after diagnosis, for a total of 1616 lesion-years. Thirty-seven (7.5%) CCMs bled during follow-up, leading to an overall annual rate of CCM-related symptomatic hemorrhage of 2.3% (95% CI 1.7%–3.2%). Eighty-two patients harboring 91 CCMs (16.8%) were on ATM. When stratified for ATM, the annual rates of hemorrhage were 0.7% (95% CI < 0.01% to 4.2%) for the lesions in patients on ATM versus 2.5% (95% CI 1.8%–3.4%) for those not on ATM. ATM was not found to be associated with either an increased risk of CCM-related hemorrhage at presentation (p = 0.355) or an increased risk of CCM-related hemorrhage (first or subsequent hemorrhage) in multivariate descriptive (p = 0.912) and survival (p = 0.145) analyses.CONCLUSIONSThe use of ATM does not seem to be associated with an increased risk of hemorrhage in patients diagnosed with CCMs.

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.

Surgical Resection Can Be Successful in a Large Fraction of Patients With Drug-Resistant Epilepsy Associated With Multiple Cerebral Cavernous Malformations

Neurosurgery ◽  
2013 ◽  
Vol 74 (2) ◽  
pp. 147-153 ◽  
Author(s):  
Christian von der Brelie ◽  
Marec von Lehe ◽  
Anna Raabe ◽  
Pitt Niehusmann ◽  
Horst Urbach ◽  
...  
Keyword(s):  
Surgical Treatment ◽  
Epilepsy Surgery ◽  
Large Fraction ◽  
Cerebral Cavernous Malformations ◽  
Drug Resistant ◽  
Cavernous Malformations ◽  
Predictive Parameters ◽  
Class 1 ◽  
Drug Resistant Epilepsy

Abstract BACKGROUND: Multiple cerebral cavernous malformations (mCCMs) are known as potentially epileptogenic lesions. Treatment might be multimodal. Management of patients with mCCMs and epilepsy is challenging. OBJECTIVE: To evaluate (1) algorhythmic therapeutic sequences in patients with epilepsy associated to mCCMs, (2) whether there are predictive parameters to anticipate the development of drug-resistant epilepsy, and (3) seizure after epilepsy surgery compared to conservatively-treated drug-resistant patients. METHODS: All inpatients and outpatients with epilepsy associated to mCCMs from 1990 to 2010 and follow-up &gt;12 months available were retrospectively analyzed. RESULTS: Twenty-three patients matched inclusion criteria. Epilepsy became drug-resistant in 18/23 (78%) patients. No predictors were found for development of drug-resistant epilepsy. Median follow-up for both groups was 7.8 years. Nine patients did not qualify for surgical therapy and were treated conservatively. One patient of this cohort (11%) was seizure-free (International League Against Epilepsy [ILAE] class 1). Surgical treatment was performed in 9 patients; 7/9 (78%) of these patients were seizure-free (ILAE class 1) after epilepsy surgery for at least 12 months compared with 1/9 patients in the non-operated group. In 7/9 cases (78%) the largest CCM was resected. In 8/9 (89%) not all CCMs were resected. CONCLUSION: After initial diagnosis of epilepsy associated to mCCMs, a primary conservative approach is reasonable. Surgical treatment can be successful in a large fraction of cases with drug-resistant epilepsy where an epileptogenic lesion is identified. Cases where surgery is not undertaken are likely to remain intractable.

LONG-TERM OUTCOME OF PATIENTS WITH MULTIPLE CEREBRAL CAVERNOUS MALFORMATIONS

Neurosurgery ◽  
2009 ◽  
Vol 65 (3) ◽  
pp. 450-455 ◽  
Author(s):  
Juri Kivelev ◽  
Mika Niemelä ◽  
Riku Kivisaari ◽  
Reza Dashti ◽  
Aki Laakso ◽  
...  
Keyword(s):  
Family History ◽  
De Novo ◽  
Good Condition ◽  
Neurological Deficits ◽  
Cerebral Cavernous Malformations ◽  
Cavernous Malformations ◽  
Long Term Outcome ◽  
History Of ◽  
The Mean

Abstract OBJECTIVE Multiple cerebral cavernous malformations (MCCMs) typically occur in patients with a family history of these lesions. Literature on MCCMs is scarce, and little is known about their natural history. METHODS Of 264 consecutive patients with cerebral cavernomas treated at the Department of Neurosurgery, Helsinki University Central Hospital, in the past 27 years, 33 patients had MCCMs. Lesions were categorized according to the Zabramski classification scale. Follow-up questionnaires were sent to all patients. Outcome was assessed using the Glasgow Outcome Scale, and amelioration of epilepsy was assessed using the Engel scale. All clinical data were analyzed retrospectively. RESULTS The mean age of patients at diagnosis was 44 years. Sex presentation was almost equal. Nine percent of all patients had a family history of the disease. Patients presented with epilepsy, acute headache, and focal neurological deficits. MCCMs were incidental findings in 2 patients. Altogether, 416 cavernomas were found: 70% supratentorial and 30% infratentorial. Fifteen patients had symptomatic hemorrhage before admission to our department. Surgery was performed on 18 patients. In most cases, the largest cavernoma was removed. Postoperatively, 1 patient experienced temporary hemiparesis, and another developed permanent motor dysphasia. No mortalities occurred. The mean follow-up time was 7.7 years. Twenty-six patients (79%) were in good condition. Among patients with epilepsy who underwent lesionectomy, 70% had an Engel class I outcome. On follow-up magnetic resonance imaging, 52 de novo cavernomas were found. CONCLUSION Surgical treatment of patients with MCCMs is safe. An extirpation of the clinically active cavernoma prevents further bleedings and improves outcome of epilepsy.

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