CCM1 gene mutations in families segregating cerebral cavernous malformations

Cerebral cavernous malformations (CCM) are vascular anomalies, sometimes inherited as an autosomal dominant trait, which can cause strokes and seizures. Recently, mutations of the CCM1 gene (chromosome 7q) have been found in a subset of families. The authors found 10 new mutations by screening 29 families and five seemingly sporadic cases of CCM. The mutations predicted truncation of the Krit1 mRNA encoded by CCM1, supporting the contention that CCM result from loss of Krit1 protein function and the possibility that this protein acts as a tumor suppressor.     

CCM3 mutations are uncommon in cerebral cavernous malformations

Cerebral cavernous malformations (CCMs) are characterized by abnormally enlarged capillary cavities without intervening brain parenchyma. Mutations in the gene PDCD10 have been found in CCM families linked to the CCM3 locus. The authors screened this gene in 15 families that did not have a CCM1 or CCM2 mutation. Only two novel mutations were found, suggesting that mutations in this gene may only account for a small percentage of CCM familial cases.     

Ultrastructural analysis of vascular features in cerebral cavernous malformations

Objective

Investigation of the structure of vascular malformations highlights the pathogenic mechanisms underlying their clinical behavior. One of the vascular malformations is called cerebral cavernous malformation (CCM). However, the ultrastructural features of the vascular malformations are not defined in detail.

Methods

We aimed to investigate the ultrastructural features of CCMs using transmission (TEM), scanning (SEM) electron microscopy, and also immunohistochemistry methods with antibodies against CCM proteins such as CCM2 and CCM3. CCM tissues (n = 6) microsurgically excised from patients for conventional indications.

Results

CCM2 and CCM3 were strongly detected in the vascular endothelium. However, there was a very weak immunostaining in stroma. SEM observations revealed that there were ruptures and damages in the luminal endothelium, possibly due to the damage of intercellular junctions. TEM observations also showed a few ruptures and detachments between the endothelium and basal lamina as observed with partially damages and disconnections. The architecture of pericytes showed protrusions and shrinkages. Our results suggest that the thin vessel walls of CCMs were lacking of subendothelial support and intact basal lamina underlying the endothelial cells.

Conclusion

This study is so far the first study attempting to show human CCM lesions with SEM. We believe that an understanding of the ultrastructural features of these lesions by light and electron microscopy techniques would help to understand the pathology of these diseases.     

颅内海绵状血管瘤的外科治疗

目的 总结颅内海绵状血管瘤(CMs)的临床特点、影像学特征和治疗原则,为颅内CMs的临床诊治提供依据.方法 对2005年9月至2011年9月西京医院、海军总医院显微手术切除的127例颅内CMs的临床资料进行回顾性分析.结果 本组127例,男63例、女64例,年龄5～68岁.颅内病灶共139个,其中脑内病灶133个(幕上103个,幕下30个),脑外病灶6个,均位于左侧海绵窦.癫痫是最常见临床症状(58/127),其他症状包括头痛、脑神经功能障碍等.脑内CMs的典型MRI特征为“桑葚”样团块影,而脑外CMs的MRI特征与脑内CMs不同.所有病例均手术治疗,5例巨大病变有少部分残留,其余病灶均全切;1例遗留有轻偏瘫,生活可自理;有癫痫症状的58例患者中,4例术后仍需口服抗癫痫药物治疗,偶有癫痫发作,其余患者症状消失.结论 脑内CMs是最常见的颅内CMs类型,主要位于幕上,手术治疗能取得良好疗效,是首选治疗方法.脑外CMs少见,主要位于海绵窦区,手术和放疗均有良好的效果.     

Epilepsy surgery in patients with multiple cerebral cavernous malformations

PurposeCerebral cavernous malformations (CCMs) are frequently associated with intractable epilepsy. Whereas surgery indication in single CCMs is clear, data regarding the efficacy of epilepsy surgery in patients with multiple CCMs are scarce. We sought to clarify diagnostic requirements and postoperative outcome in patients with multiple CCMs and refractory epilepsy.MethodsRetrospective analysis of clinical records of hospitalized patients who underwent comprehensive diagnostic work-up including long-term video-EEG monitoring.ResultsFrom a total of 63 consecutive patients with CCMs and medically refractory epilepsy, 11 (17%) had multiple CCMs and underwent epilepsy surgery. There were three females and eight males. Mean age at epilepsy onset was 28.3 years (S.D. 12.3), and at epilepsy surgery, 40.7 years (S.D. 10.3). On average, each patient had 3.7 (S.D. 2.2) supratentorial CCMs. In all cases we identified only one epileptogenic zone. The epileptogenicity was higher for the CCMs located within the temporal lobe. At 2 years follow-up, the outcome according to the Engel classification was Ia (seizure-free) in nine patients (81.8%) and IIb (rare seizures) and IVc (worsening) in two patients, respectively. In one patient, a dual pathology was present and, in another case, de novo appearance of CCMs was demonstrated.ConclusionsOur results show that postoperative outcome in patients with multiple CCMs can be as good as in those with single malformations if proper presurgical identification of the epileptogenic CCMs is done. The possibility of the novo appearance of CCMs or dual pathology may occur and may affect long-term outcome negatively.     

Genotype-phenotype correlations in cerebral cavernous malformations patients

OBJECTIVE: To compare clinical features of CCM1, CCM2, and CCM3 mutation carriers. METHODS: A detailed clinical and molecular analysis of 163 consecutive cerebral cavernous malformation (CCM) families was performed. RESULTS: A deleterious mutation was detected in 128 probands. Three hundred thirty-three mutation carriers were identified (238 CCM1, 67 CCM2, and 28 CCM3). Ninety-four percent of the probands with an affected relative had a mutation compared with 57% of the probands with multiple lesions but no affected relative (p < 0.001). The number of affected individuals per family was lower in CCM3 families (p < 0.05). The proportion of patients with onset of symptoms before 15 years of age was higher in the CCM3 group (p < 0.0025). Cerebral hemorrhage was the most common initial presentation in CCM3 patients. The average number of T2-weighted imaging lesions was similar in the three groups, in contrast with a significantly lower number of gradient-echo sequence lesions in CCM2 patients (p < 0.05). The number of gradient-echo sequence lesions increased more rapidly with age in CCM1 than in CCM2 patients (p < 0.05). INTERPRETATION: Despite similarities among the three groups, there is a significantly lower number of affected individuals in CCM3 pedigrees, CCM3 mutations may confer a higher risk for cerebral hemorrhage, particularly during childhood, and the increment of gradient-echo sequence lesions with age differs between CCM1 and CCM2 patients.     

Cerebral cavernous malformations: mutations in Krit1

OBJECTIVE: To find mutations in the recently identified additional exons of the Krit1 gene that causes CCM1, a disease characterized by the formation of cerebral cavernous malformations (CCM). To determine the relative frequency with which Krit1 mutations cause CCM as well as recharacterize the mutations reported in the literature. METHODS: Twenty-seven families and 11 apparently sporadic individuals affected with CCM were screened for mutations in the Krit1 gene. The gene was screened by single stranded conformation polymorphism, and variants were sequenced. Familial segregation of the mutations was determined. RESULTS: In familial samples, two new mutations in the novel upstream exons and six additional mutations in the previously identified exons were identified. No mutation was found in any of the sporadic individuals. CONCLUSIONS: Results demonstrate that the frequency of mutations found in Krit1 is 47% in the families studied and the frequency may increase as more mutations are detected. Mutations are evenly distributed in the gene and do not seem to be limited to structural domains present in Krit1. This is in accordance with the model that Krit1 could be a tumor suppressor gene.     

Clinical features and microsurgical treatment of pediatric patients with cerebral cavernous malformation

The aim of the present study was to describe the clinical features and to evaluate the surgical treatment outcomes of pediatric patients with cerebral cavernous malformations (CCM). We investigated 85 children (53 boys and 32 girls), aged from 6 months to 17.9 years with CCM. Seizures and symptomatic hemorrhages, which were the most frequent symptoms, occurred in 81 patients. Nine patients had a positive family history of CCM. Eighty patients underwent microsurgical treatment after strict operative indications were met. Neuronavigation, combined with intraoperative ultrasonography or functional MRI, was used for precise localization of the lesions. The principles of minimally invasive techniques were followed during surgery. A total of 89 lesions were removed in 80 patients, and there were no deaths. During their hospital stay, only nine patients suffered from postoperative seizures, which were controlled with medication. Postoperative neurological deficits improved in 27 patients, were unchanged in nine, and worsened in two. With the help of advanced neuroimaging, a satisfactory surgical outcome was achieved for 10 lesions located in eloquent brain areas and four lesions in the brain stem. A follow-up study of 66 patients showed that all of these patients remained seizure-free, and nine patients with postoperative neurological deficits gradually recovered. Microsurgical treatment should be performed early for pediatric patients with CCM. Accurate localization of the lesions and the use of minimally invasive techniques and functional MRI monitoring were the key features of the surgical procedures.     

Germline mutations in the CCM1 gene, encoding Krit1, cause cerebral cavernous malformations

Mutations in the Kritl gene have been recently discovered as the cause of hereditary cerebral cavernous angioma. We sought the possibility that de novo, noninherited mutations of Kritl also cause cavernous angioma. A patient with two cerebral malformations carries a heterozygous deletion of two base pairs (741delTC) in exon VI of the Kritl gene. The deletion initiates a frameshift mutation that, 23 amino acids downstream, encodes a TAA stop triplet replacing a CAT triplet of histidine at exon VII (H271X). Magnetic resonance images of the parents were normal, neither parent carries the 741delTC mutation, and both bear the wild-type sequence of exon VI. These findings document a de novo germline mutation in Kritl gene that causes cerebral cavernous malformations.     

Genetics of cerebral cavernous malformations

The past few years have seen rapid advances in our understanding of the genetics and molecular biology of cerebral cavernous malformations (CCM). This article summarizes the recent cloning of the CCM1, CCM2, and CCM3 genes, which are responsible for autosomal dominant CCM, and also describes current hypotheses for their roles in integrin and p38 mitogen-activated protein kinase-mediated regulation of angiogenesis. A mouse model of CCM has been generated by mutation of the Ccm1 gene, and it indicates a role for that protein in arterial development. Future studies will probably focus on integration of data from each of the three CCM genes into a single model of the pathogenesis of cavernous malformation.     

CCM1 mutation screen of sporadic cases with cerebral cavernous malformations

Cerebral cavernous malformations (CCM) are CNS vascular anomalies associated with seizures, headaches, and hemorrhagic strokes. The CCM1 gene was screened in 35 sporadic cases with either single or multiple CCM. It was found that 29% of the individuals with multiple CCM have a CCM1 mutation, whereas cases with only one malformation have none. Sporadic cases with multiple malformations warrant the same approach as individuals who have a familial history of CCM.     

Prospective follow-up of 33 asymptomatic patients with familial cerebral cavernous malformations.

BACKGROUND: Cerebral cavernous malformation (CCM) is one of the most common vascular malformations of the CNS. Familial CCM are increasingly diagnosed, but little is known about their natural history, especially in asymptomatic patients. OBJECTIVE: To determine the degree of spontaneous evolution of familial CCM in a population of 33 symptom-free patients. METHODS: During a previous national survey, the authors analyzed the clinical and MRI features of 173 patients from 57 unrelated French families, including 73 asymptomatic subjects. Of these 73 subjects, 33 prospectively underwent two serial clinical and MRI examinations. Cerebral MRI systematically included spin echo and gradient echo sequences. Occurrence of clinical symptoms and MRI changes of CCM, namely, hemorrhage, change in signal intensity, change in size, and appearance of new lesions, were recorded by means of comparison of the first and last MRI examinations. RESULTS: The 33 patients (234 CCM, mean 7.1 lesions/subject, range 1 to 85 lesions/subject) were followed during a mean period of 2.1 years (range 0.5 to 4.5 years). Two patients became symptomatic: One presented with brainstem hemorrhage and one with partial seizure. Comparison of the two serial MR images found changes in 15 patients (46%): 1) Bleeding occurred in three type II lesions (1.3%) in three patients (9.1%); 2) 30 new lesions appeared in 10 patients (30.3%); 3) change in signal intensity was observed in one lesion (0.4%) in one patient (3%); and 4) increase in size was observed in four lesions (1.7%) in three patients (9.1%). CONCLUSIONS: This prospective study confirms the dynamic nature of CCM. The appearance of new lesions in 30% of patients has to be retained as a hallmark of the familial condition.     

Role of aspirin and statin therapy in patients with cerebral cavernous malformations

Stagnant blood flow and organizing thrombus are intralesional components of patients with cerebral cavernous malformations (CCM). Stasis and inflammation are mechanisms of growth, lesional instability and acute hemorrhages with or w/o symptoms. We evaluate the association of pre-diagnostic aspirin and/or statin use with acute hemorrhages at diagnosis. Patients with a CCM diagnosis were identified and categorized according to their medications on admission into four groups (no therapy, statin, aspirin, combined). The primary outcome was an acute hemorrhage (with or w/o symptoms) at diagnosis reported in a standardized manner from the T2 weighted magnetic resonance image. A multivariate generalized linear mixed models (GLMM) was utilized to conduct per-lesion analysis. We identified 446 patients with 635 lesions. An acute hemorrhage at diagnosis was observed in 31% of the patients. There were 328 patients without statin or aspirin therapy, 34% of whom presented with acute hemorrhage. Of patients on aspirin therapy at diagnosis, 25% presented with hemorrhage. Of patients on statin therapy, 26% had a hemorrhage at diagnosis. Combined therapy in 44 patients demonstrated a lower proportion of patients with acute hemorrhages (7 patients, 16% incidence). A GLMM showed that patients in the combined therapy group to have significantly lower odds of having an acute hemorrhage at diagnosis compared to the reference group of no therapy (OR 0.24; 95% CI 0.09–0.59; P = 0.002). Patients with a CCM receiving therapy with both aspirin and statins were less likely to present at diagnosis with acute hemorrhage.     

Vascular permeability in cerebral cavernous malformations

Patients with the familial form of cerebral cavernous malformations (CCMs) are haploinsufficient for the CCM1, CCM2, or CCM3 gene. Loss of corresponding CCM proteins increases RhoA kinase-mediated endothelial permeability in vitro, and in mouse brains in vivo. A prospective case-controlled observational study investigated whether the brains of human subjects with familial CCM show vascular hyperpermeability by dynamic contrast-enhanced quantitative perfusion magnetic resonance imaging, in comparison with CCM cases without familial disease, and whether lesional or brain vascular permeability correlates with CCM disease activity. Permeability in white matter far (WMF) from lesions was significantly greater in familial than in sporadic cases, but was similar in CCM lesions. Permeability in WMF increased with age in sporadic patients, but not in familial cases. Patients with more aggressive familial CCM disease had greater WMF permeability compared to those with milder disease phenotype, but similar lesion permeability. Subjects receiving statin medications for routine cardiovascular indications had a trend of lower WMF, but not lesion, permeability. This is the first demonstration of brain vascular hyperpermeability in humans with an autosomal dominant disease, as predicted mechanistically. Brain permeability, more than lesion permeability, may serve as a biomarker of CCM disease activity, and help calibrate potential drug therapy.     

Intramedullary cavernous malformations: Clinical features and surgical technique via hemilaminectomy

Objective

The purpose of this study was to define the clinical features and the surgical technique of unilateral hemilaminectomy for treating intramedullary cavernous malformations.

Materials and methods

Retrospective chart was performed in 16 patients with histologically diagnosed intramedullary cavernous malformations. All patients were treated with unilateral hemilaminectomy and microsurgical resection of the malformations. The pre- and postoperative neurological state was evaluated using Frankel scale.

Results

There were nine females and seven males (mean age 38 years) harbouring symptomatic intramedullary cavernous malformations. The annual retrospective haemorrhage rate was 3.1% per patient/year. All cavernous malformations were completely resected. Twelve of 16 patients experienced the improvement of the neurological state and in four patients, clinical features remained unchanged during the follow-up period. Static and dynamic plain radiograph film showed none of them had spinal deformity or spinal instability.

Conclusion

According to the defined bleeding risk, symptomatic and MRI-morphologically growing intramedullary cavernous malformations should be totally surgically removed, to avoid the recurrence and rebleeding of the residue. A least traumatic myelotomy, as well as a meticulous microsurgical technique and the intraoperative somatosensory evoked potentials monitoring, together with selection of a minimally invasive microsurgical approach (hemilaminectomy), leads to a favourable outcome and prevents additional morbidity.     

Imaging features of spinal epidural cavernous malformations

Cavernous angioma or cavernoma is a vascular malformation that may affect any area in the neuraxis. Epidural location is very rare and therefore seldom considered in the differential diagnosis of spinal cord compression. We report two cases of epidural cavernous angiomas. The first case is a solitary and purely epidural dorsal cavernous angioma without foraminal expansion or bone modification causing spinal cord compression in a 35 year old woman. The second case is a solitary epidural dorsal cavernous angioma with foraminal extension causing spinal cord compression in a 56 year old woman. Histological confirmation is available for both cases. We describe the MRI features of this lesion insisting on its differential diagnosis on imaging.     

有占位效应未破裂脑动静脉畸形的临床特点 (附31例报告)

目的　探讨有占位效应未破裂脑动静脉畸形 (cerebralarteriovenousmalformation ,cAVM)的临床特点与产生的原因。方法　分析 31例未破裂cAVM的临床资料、影像学表现及脑血管造影表现 ,对有占位效应cAVM和无占位效应cAVM的特点进行对比研究。结果　发现 11例有占位效应cAVM ,占该组病人的 35 5 % ,其病灶体积 [(72±36 )cm3 ]明显大于无占位效应cAVM[(2 2± 2 0 )cm3 ],Spetzler Martin(SM)分级多为Ⅳ～Ⅴ级 (与无占位效应组比较分别为 8/ 11和 7/ 2 0 ) ;病灶内多见扭曲扩张的静脉或静脉球 (分别为 9/ 11和 2 / 2 0 ) ;血管造影时造影剂通过病灶时间 [(0 .95± 0 .14 )s]长于无占位效应cAVM[(0 .78± 0 .15 )s],并常见静脉滞留现象。结论　cAVM占位效应并不一定是出血的表现 ,有占位效应的cAVM常常体积较大、SM分级高。占位效应的产生是多种因素共同作用的结果 ,其中病灶内扭曲扩张的静脉或静脉球、病灶的体积、引流静脉回流不畅是产生占位效应的主要因素。     

脑多发海绵状血管畸形的手术治疗

目的脑多发海绵状血管畸形手术治疗报道少见,探讨脑多发海绵状血管畸形患者的临床特征及手术治疗效果。方法回顾分析39例手术治疗脑多发海绵状血管畸形病例,采用改良MRS评分对患者神经功能状态进行评估。配对T检验对术前与随访时MRS评分进行比较,用Pearson相关分析对年龄、病变数量、术前MRS评分等对预后的影响因素进行相关性分析。结果 1例小脑脚海绵状血管畸形患者术后出现不全性面瘫,1例桥脑病变患者术后出现肢体偏瘫,经治疗后均逐渐好转。平均随访29.5月,无再次出血患者。随访时16例(41%)患者神经功能状态较术前明显改善,23例(59%)较前无变化,无病情加重患者。经统计学分析,术前与随访时MRS评分比较P=0.01,有统计学意义。性别、年龄、首发症状距手术时间、病变数量、出血次数、随访时间与预后不相关。手术病变部位(P=0.02)及术前MRS(P=0.01)与预后相关。结论脑多发海绵状血管畸形患者行致病病变切除多数患者效果良好,手术病变部位及术前MRS是影响预后的相关因素。